Effects of Statin and Ezetimibe Association on Kinetics of Artificial Chilomicrons: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of Statin and Ezetimibe Association on Kinetics of Artificial Chilomicrons (NCT00481351), a randomized phase 4 study. The primary outcome is Low Density Lipoprotein.

2. Clinical Question

The registry concerns men with stable coronary heart disease and asks how lipid measures, including low-density lipoprotein (LDL), differ between two treatment groups. Its background also focuses on the removal kinetics of artificial chylomicrons, a laboratory measure that the registry relates to coronary heart disease and LDL-C levels.

The clinical question is therefore a comparison of the recorded group regimens at the stated endpoint, rather than a comparison of a single drug dose throughout the trial. The registry also describes a study objective involving artificial chylomicron removal kinetics, but LDL is the posted primary outcome. The registry record does not give a fuller explanation for selecting LDL as the primary endpoint or specify how the endpoint relates to the kinetic measurements.

3. Trial Design

This is a Phase 4, randomized, open-label, parallel-group trial sponsored by the University of Sao Paulo. The registry lists coronary heart disease as the condition. The study started in 2007-06, reached primary completion in 2010-01, and is marked completed.

The brief summary describes a planned study of 26 outpatients and an initial random allocation of 13 participants to each treatment group. The registry enrollment is 25. In the posted LDL results, the Ezetimibe group has 13 participants and the Simvastatin group has 12. The registry record does not explain the difference between the planned and recorded numbers, or report participant flow, withdrawals, or reasons for any difference in group counts.

The arm descriptions outline different sequences. The Ezetimibe group description starts with a six-week washout, then lists six weeks of ezetimibe 10 mg once a day and a further six weeks of ezetimibe 10 mg plus simvastatin 20 mg. The Simvastatin group description lists six weeks of simvastatin 20 mg once a day followed by six weeks of simvastatin 80 mg once a day. The brief summary also describes a washout and treatment sequence, but its account is incomplete. The registry record does not resolve the timing and sequence details beyond these descriptions.

Masking is listed as none. The parallel model indicates separate groups rather than a crossover allocation in the registry's design classification. The registry record does not report the randomization method, allocation concealment, original sample-size justification, or the detailed statistical plan. Results are reported at 12 weeks for the primary outcome and for some secondary outcomes; the record does not provide enough detail to reconstruct all study visits or the analysis population.

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Low Density Lipoprotein, measured over 12week.

The primary endpoint is low-density lipoprotein, reported as a mean in mg/dl with standard deviation at 12 weeks. LDL is a blood lipid concentration: the mean describes the group’s central level, while the standard deviation describes how spread out participant values are around that mean. The endpoint therefore summarizes the measured LDL levels in each group rather than the artificial chylomicron removal rate itself.

The registry background notes a relationship between LDL-C levels and removal of chylomicron remnants measured with artificial chylomicrons. That context makes LDL relevant to the topic of the trial, but the registry record does not give a specific rationale for naming LDL as the primary endpoint or explain whether the kinetic measure was intended to be primary in an earlier protocol. The primary outcome description contains no additional endpoint definition or population detail.

At the stated measurement time, the posted group means are 74.85 mg/dl for Ezetimibe and 71.92 mg/dl for Simvastatin. The posted mean difference, defined as Simvastatin minus Ezetimibe, is -2.93 mg/dl. This contrast describes the observed group means; it does not by itself establish that the regimens caused a difference. Its uncertainty and the small group sizes matter when interpreting the estimate.

7. Results Posted in the Registry

• Group 2 Simvastatin: mean 71.92 versus 74.85 on control; difference -2.93 (95% CI -15.52 to 9.66), standardized effect d = -0.18; z-test p = 0.648.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Alanine Aminotransferase

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group 2 Simvastatin: mean 18.33 versus 30.46 on control; difference -12.13 (95% CI -21.99 to -2.27), standardized effect d = -0.94; z-test p = 0.016.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Group 2 Simvastatin than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

CPK

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group 2 Simvastatin: mean 131.00 versus 169.00 on control; difference -38.00 (95% CI -113.73 to 37.73), standardized effect d = -0.39; z-test p = 0.325.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 Simvastatin and the control. The interval gives the range of effects that remain compatible with the data.

Total Cholesterol

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group 2 Simvastatin: mean 148.29 versus 152.61 on control; difference -4.32 (95% CI -23.04 to 14.40), standardized effect d = -0.18; z-test p = 0.651.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 Simvastatin and the control. The interval gives the range of effects that remain compatible with the data.

The secondary results give a mixed pattern rather than a consistent repetition of the primary LDL comparison. The three numerical secondary outcomes are alanine aminotransferase, CPK, and total cholesterol. Their estimates and uncertainty intervals differ: one interval excludes zero, while the other two include zero. The registry also names triglyceride fractional clearance rate and high-density lipoprotein as secondary outcomes, but numerical results for those measures are not reported in the registry record.

These outcomes provide related laboratory context, but they do not replace or resolve the primary LDL result. The primary result is itself imprecise, and the secondary measures describe different endpoints. A pattern in one laboratory measure does not establish a corresponding pattern in another measure, or in artificial chylomicron kinetics. The record does not report a formal analysis tying secondary outcomes to the primary endpoint or to one another.

The secondary p-values are unadjusted. When multiple outcomes are tested, the chance of at least one apparently unusual result can increase; this is a general statistical concern, not a finding that any particular secondary result is false. The registry record does not report a hierarchy of outcomes, a multiplicity adjustment, or a prespecified plan for interpreting secondary tests. Accordingly, a single secondary p-value should carry less weight than a clearly prespecified primary comparison and should be read alongside its estimate, interval, and the broader set of outcomes.

The record’s incompleteness also limits comparisons across the intended outcome set. Without numerical results for all listed secondary outcomes, readers cannot assess whether the posted measures represent the full planned pattern. Nor does the registry record state whether the unreported measures were not collected, were collected but not analyzed, or were omitted from the results record. Those explanations are not reported in the registry record and should not be inferred.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Triglyceride Fractional Clearance Rate
• Alanine Aminotransferase
• CPK
• Total Cholesterol
• High Density Lipoprotein

9. Statistical Interpretation

10. Statistical Methods Explained

The posted continuous outcomes are expressed as group means and standard deviations. A mean is the arithmetic average of the measured values within a group. A standard deviation describes variability among individual observations, not uncertainty in the mean itself. Standard errors and confidence intervals address uncertainty in estimated quantities and depend on sample size as well as variability. These are general statistical distinctions; the registry reports the outcome summaries but does not give a comprehensive description of its analysis methods.

What does the mean difference represent?

The primary contrast is defined as the Simvastatin group mean minus the Ezetimibe group mean. On that scale, a negative value means the recorded mean is lower in the Simvastatin group; a positive value means it is higher. The reported estimate is -2.93 mg/dl. The same direction convention is used for the posted secondary mean differences. This is a simple, unadjusted comparison of group summaries, not an estimate adjusted for baseline values or other covariates. The registry record does not report adjusted analyses.

Random allocation is intended to reduce systematic differences between groups at the point of assignment. In a randomized study, a difference in outcome averages can be interpreted as a treatment-group contrast under appropriate conduct and analysis assumptions. Randomization does not guarantee identical groups in a small study, and it does not address possible problems such as incomplete follow-up or missing outcome data. The registry record does not report allocation concealment, baseline outcome values, withdrawals, or missing-data procedures, so those aspects cannot be assessed from the posted record.

How should the p-value be read?

A p-value is a measure of how compatible the observed data are with a specified null hypothesis under a statistical model. It is not the probability that the null hypothesis is true, and it does not express the probability that a result arose by chance in an unrestricted sense. The primary p-value is unadjusted. The secondary p-values are also described as unadjusted comparisons; no multiplicity adjustment is reported. The record does not identify the exact test, degrees of freedom, or whether any analysis choices differed from the simple comparisons accompanying the posted summaries.

A conventional significance threshold is only meaningful in the context of a prespecified testing plan. The registry record does not report the original statistical analysis plan or a threshold specified for the trial. The value 0.05 appears among assumptions for the separate sample-size planning illustration, but that planning assumption should not be mistaken for documentation of the original trial’s analysis plan.

Why do standard deviations matter?

When participant measurements vary widely, a group mean is less precise for a fixed sample size than when measurements cluster closely around the mean. Standard deviations are therefore important context for interpreting mean differences. They describe variation in individual measurements, whereas a confidence interval describes uncertainty in an estimated group contrast. Neither the group standard deviation nor a p-value should be used alone as a measure of clinical importance.

General statistical concept: when data are more variable than a model assumes, a model that ignores that extra variation can understate uncertainty and make evidence appear more precise than it is. That issue is often called over-dispersion. The registry record does not report count-model outcomes or a model for chylomicron kinetics that would allow an assessment of over-dispersion. For the continuous outcomes posted, the displayed summaries do not establish whether distributional assumptions were checked.

What is and is not reported about the analysis?

The registry lists seven outcome measures and provides numerical summaries for the primary LDL endpoint and three secondary endpoints. The registry record lists triglyceride fractional clearance rate and high-density lipoprotein among secondary outcomes, but numerical results for those measures are not reported in the record. The numerical comparisons presented for the available continuous summaries are unadjusted recalculations from posted means, standard deviations, and group sizes. The registry record reports zero analyses in its analyses count and no reported analyses for the secondary outcomes. No sponsor analysis that differs from these calculations is reported, and the discrepancy indicator is false.

The registry does not report whether the endpoint analysis followed intention-to-treat, per-protocol, or another population definition. It does not report how missing values were handled, whether outcomes were transformed, or whether the analysis accounted for repeated measures or the sequential regimens. These omissions prevent a full audit of the statistical procedure. The posted contrasts are useful descriptive comparisons, but they should not be mistaken for a complete protocol-based analysis.

General statistical concept: confidence intervals convey a range of estimates compatible with the data and the assumptions used to calculate them. Wider intervals indicate less precision. A p-value compresses evidence into a single measure and does not show the range of plausible effect sizes, which is why the estimate and interval are important alongside it. The registry does not state a confidence level for the posted intervals, so no particular coverage level is assigned in this interpretation.

11. Confidence Intervals and Precision

The primary mean difference is -2.93 mg/dl, with an interval from -15.52 to 9.657 mg/dl. Because the interval crosses zero, the posted data are compatible with a negative difference and with a positive difference. The interval also spans values appreciably farther from zero than the point estimate. That breadth indicates limited precision about the direction and magnitude of the population contrast.

In general, a confidence interval describes uncertainty around an estimated quantity under the method and assumptions used to construct it. A narrower interval gives a more precise estimate; it does not guarantee that the estimate is unbiased or clinically important. The registry record does not state the confidence level or fully describe the interval method. The interval should therefore be interpreted as the uncertainty range reported with the posted comparison, without assigning it an unreported coverage level.

The group standard deviations for LDL are 16.76 mg/dl and 15.35 mg/dl, with 13 and 12 participants in the groups. These summaries show why an estimate based on a small number of observations can remain uncertain even when group means are close. The interval is not evidence that all values within it are equally likely, nor does it establish that differences inside the interval are unimportant. The registry record does not specify a clinically important threshold for LDL.

Secondary intervals also vary in their precision. The alanine aminotransferase interval lies below zero, while the CPK and total cholesterol intervals include zero. Those comparisons are unadjusted and are not a substitute for a prespecified multiplicity strategy. In particular, a result whose interval excludes zero should not automatically be treated as confirmatory when several outcomes are examined and the testing plan is not reported.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for the continuous-outcome comparisons, not total events. They are illustrations based on the observed effect in each comparison and are not the enrollment targets originally used to design this trial. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial’s sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the estimated number of participants per arm for a planning scenario designed to have an 80% chance of detecting the chosen effect under those assumptions. The 90% power column gives the corresponding number for a 90% chance. These are prospective planning quantities, not probabilities calculated from the completed trial’s results. They do not establish the probability that this trial detected an effect, and they are not observed power.

Rows using 100%, 75%, or 50% of the observed effect illustrate how the planned detectable difference changes. A smaller target effect is harder to distinguish from random variation, so more participants are needed to achieve the same power under the same assumptions. The numbers depend on the observed effect and variability in these data; they should not be treated as reliable design recommendations without independent clinical choices about the effect worth detecting and an appropriately specified design.

The sample-size planning calculations use equal allocation even though the posted LDL groups contain 13 and 12 participants. The registry record does not say that the original trial was planned using these calculations. The illustrations also do not account for any unreported features such as missing outcomes or analysis adjustments. Their role is to show how sample-size needs change under the stated assumptions, not to explain why the trial enrolled its recorded number.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -2.930; pooled standard deviation σ = 16.101.
2. n = 2 × (1.96 + 0.842)² × 16.101² / -2.930² = 474.0, rounded up to 475 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -2.92999999999999                      # observed difference in means
sigma <- 16.1010649121214                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(481351)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 475 (80% power), 635 (90% power)
 75% of observed effect: n per arm = 843 (80% power), 1,129 (90% power)
 50% of observed effect: n per arm = 1,897 (80% power), 2,539 (90% power)
power.t.test: 475 
Simulated power at n = 475 per arm: 0.798 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies LDL as the primary outcome and lists secondary outcomes, but it does not report a detailed plan for handling multiple comparisons. The posted p-values are unadjusted. No multiplicity correction, outcome hierarchy, gatekeeping procedure, or prespecified confirmatory role for the secondary endpoints is reported in the registry record.

General statistical concept: testing many outcomes can increase the chance of obtaining at least one small p-value even when no underlying difference exists. Adjustment procedures or a clearly defined testing sequence can address that issue, but they may also change how individual p-values and intervals should be interpreted. Without a reported plan, the secondary comparisons are best treated as descriptive or exploratory evidence rather than as a collection of independent confirmations. The registry record does not indicate whether the trial investigators used a multiplicity procedure outside the record.

Missing-data methods and analysis populations are also not reported in the registry record. The posted group sizes are 13 and 12 for the primary endpoint, but the record does not say whether these represent all randomized participants, all participants with measured LDL, or a particular analysis population. It does not report withdrawals, reasons for missing measurements, imputation, or sensitivity analyses. As a result, the effect of missingness on the estimates cannot be assessed.

The record does not specify whether the main analysis was intention-to-treat, per-protocol, or based on participants with available endpoint data. It also does not describe adjustment for baseline measures or how the successive treatment periods were handled. The reported group summaries can be compared as posted, but they cannot answer these analysis questions. The sample-size planning assumptions do not fill the gap: they are planning illustrations and are not a substitute for the trial’s unreported original statistical plan.

15. What the Result Does, and Does Not, Mean

The posted primary result describes average LDL levels in the two recorded groups at 12 weeks. The Simvastatin group mean was lower than the Ezetimibe group mean by the posted estimate, but the interval is broad and includes differences in either direction. The result is therefore uncertain about the direction and size of the underlying group contrast. It does not establish equivalence, because no equivalence margin or equivalence analysis is reported.

The registry record describes random assignment, but the reported treatment sequences differ between groups. The resulting contrast applies to those recorded regimens and endpoint timing, not necessarily to a comparison of isolated drugs under otherwise identical exposure. The record does not provide enough detail to determine how all phases of the regimens align with the 12-week LDL measurement. That limits how specifically the comparison can be attributed to a single treatment component.

The result does not directly answer whether artificial chylomicron removal kinetics differ, because the posted primary outcome is LDL and numerical results for the listed triglyceride fractional clearance measure are not reported. Nor does the record establish a clinical effect on coronary heart disease events or patient symptoms. Such outcomes are not reported as results in the information available for this trial.

The secondary findings should be read cautiously because several endpoints are considered, the p-values are unadjusted, and a multiplicity plan is not reported. Some secondary estimates are more precise than others, but they do not overturn the uncertainty in the primary comparison. Missing-data procedures and analysis populations are also not reported, further limiting assessment of how representative the posted summaries are of everyone randomized.

In general, a trial result is one estimate from one study population and design. The registry record supports a description of the posted measurements and their uncertainty; it does not justify broad conclusions about treatment performance beyond those data. It also does not provide a threshold for deciding what size of LDL difference would be clinically meaningful.

16. Why This Trial Matters Statistically

This trial is statistically instructive because the point estimate and its uncertainty tell different parts of the story. The primary estimate is modest in relation to the width of its interval, and the interval includes values on either side of zero. Reporting the estimate alone would conceal substantial uncertainty; relying on the p-value alone would also omit the range of differences compatible with the data.

The small posted group sizes make precision especially important. The registry’s planning illustrations show how the number of participants required depends on the effect size chosen for detection. In general, planning around a smaller effect requires more participants than planning around a larger effect, all else equal. Those illustrations also make clear that a completed study’s sample size should not be treated as evidence that it was designed to answer every possible effect-size question.

The trial also highlights the need to distinguish the named primary endpoint from the study’s broader scientific motivation. The background concerns artificial chylomicron kinetics, while the posted primary outcome is LDL. Without numerical results for all listed kinetic or lipid outcomes and without a reported analysis plan, readers cannot reconstruct the complete relationship between the study objective and its endpoint results.

Finally, the record illustrates why transparent reporting matters. Group sizes and means are useful, but fuller reporting of participant flow, missing-data handling, analysis populations, endpoint definitions, and multiplicity decisions would allow a more complete statistical assessment. The posted evidence remains interpretable as a limited set of group summaries and unadjusted comparisons, but its scope should remain correspondingly narrow.

17. 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 posted enrollment is 25, whereas the brief summary describes a planned 26 participants and an initial allocation of 13 per group. The posted LDL groups contain 13 and 12 participants. The registry record does not explain the difference or report a participant-flow account, making it difficult to determine how enrollment and outcome availability relate.

The registry labels the study open-label and reports no masking. It also describes sequential treatment regimens that differ between arms. The record does not fully clarify how the stated 12-week endpoint aligns with all phases of these sequences, so the endpoint contrast cannot be interpreted as a clean comparison of one drug component alone based on the posted description.

The trial is small, and the primary interval is broad. The registry record does not report the original sample-size justification, randomization details, baseline values, analysis population, missing-data methods, or a complete statistical analysis plan. It also does not provide numerical results for every listed secondary outcome. The record therefore leaves uncertainty about participant flow, analysis decisions, and the completeness of outcome reporting.

Safety information is limited in the posted results. The record lists zero serious adverse events among those at risk in both groups and zero other adverse events among 13 and 12 participants, respectively. The deaths fields are null, so a death count is not reported in the registry record. The available entries do not provide event descriptions or additional detail with which to assess safety reporting.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Effects of Statin and Ezetimibe Association on Kinetics of Artificial Chilomicrons — NCT00481351.
• Registry record last updated 2011-01-26; status last verified 2007-01.
• Results first posted 2011-01-26.
• 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.

21. Record Summary

NCT00481351 is a completed, Phase 4, randomized, open-label, parallel-group trial sponsored by the University of Sao Paulo. It enrolled 25 participants and studied men with stable coronary heart disease. The posted primary endpoint is mean LDL at 12 weeks.

The LDL means were 74.85 mg/dl for the Ezetimibe group and 71.92 mg/dl for the Simvastatin group. The unadjusted mean difference was -2.93 mg/dl, with an interval from -15.52 to 9.657 and an unadjusted p-value of 0.648. This is an imprecise comparison, and the registry record does not report a full statistical analysis plan.

Numerical results are posted for three secondary outcomes. Other listed secondary outcomes do not have numerical results reported in the registry record. Multiplicity handling, missing-data methods, analysis populations, and the original sample-size justification are not reported.