AEGR-733 and Atorvastatin 20 mg vs. Monotherapy in Moderate Hypercholesterolemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for AEGR-733 and Atorvastatin 20 mg vs. Monotherapy in Moderate Hypercholesterolemia (NCT00474240), a randomized phase 2 study. The primary outcome is Percent Change From Baseline in LDL-C at 8 Weeks.

2. Clinical Question

In practical statistical terms, the study addresses whether the observed average change in LDL-C differed across randomized groups over the stated treatment period. The endpoint is continuous, so the posted summary describes a mean and standard deviation for each arm rather than a count of participants reaching a threshold. The study title and brief summary frame the investigation around safety and cholesterol effects. These posted results address the primary lipid endpoint and adverse-event counts; they do not establish how clinically important the differences are or support conclusions about outcomes not reported in the registry record.

3. Trial Design

The registry describes a randomized, triple-masked, parallel-group phase 2 study, with placebo control. It is titled as a comparison of AEGR-733 and atorvastatin 20 mg, alone and in combination, in subjects with moderate hypercholesterolemia. The study status is completed. The sponsor is Aegerion Pharmaceuticals, Inc. The listed start is 2007-04, and the listed primary completion is 2008-10.

Six interventions are listed: placebo; atorvastatin 20 mg; AEGR-733 5 mg; AEGR-733 10 mg; AEGR-733 5 mg plus atorvastatin 20 mg; and AEGR-733 10 mg plus atorvastatin 20 mg. The arm descriptions themselves are blank in the registry record. The posted primary outcome summary gives 25 participants for placebo, 24 for atorvastatin 20 mg, 18 for AEGR-733 5 mg, 10 for AEGR-733 10 mg, 18 for AEGR-733 5 mg plus atorvastatin 20 mg, and 9 for AEGR-733 10 mg plus atorvastatin 20 mg. These are arm-level endpoint counts, not a restatement of the enrollment figure.

Randomization assigns participants to study groups by chance; masking is intended to limit the influence of knowledge of assigned treatment on participant or study-team behavior and assessment. The registry’s designation is triple masking, but the identities of the masked parties are not reported in the registry record. A parallel-group design means the listed groups are followed as separate arms rather than described as a crossover sequence. The timing of the primary measurement is after 8 weeks on study drug. Further details about treatment administration, allocation procedures, adherence, and the original sample-size rationale are not reported in the registry record.

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: Subjects who were previously on a lipid lowering therapy underwent a 5-week washout period. All subjects were on a low-fat diet (\<30% calories from fat) starting 5 weeks prior to study drug treatment and continuing for the duration of the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent To Treat

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline in LDL-C at 8 Weeks, measured over Atfer 8 weeks on study drug.

The primary endpoint is percent change from baseline in LDL-C at 8 weeks on study drug. The registry specifies a mean as the summary measure, standard deviation as the measure of dispersion, and an Intent To Treat population. Percent change expresses the change relative to a participant’s baseline value, while the reported arm mean describes the average change in that group. A negative mean represents a decrease from baseline; a more negative value represents a larger average decrease on this scale.

LDL-C is the lipid measure named by the primary endpoint, and the trial’s stated purpose concerns cholesterol in volunteers with moderately high cholesterol. A continuous endpoint preserves information about the size and direction of change rather than reducing the result to a binary outcome. Reporting the mean alongside the standard deviation gives a view of the group average and the variability of individual observations around it. The standard deviation is not the uncertainty of the mean; uncertainty in a group mean depends on both variability and the number of observations.

The time point is specific: the primary results describe the endpoint after 8 weeks on study drug, not a longer-term outcome. The endpoint alone does not describe other lipid measures, symptoms, cardiovascular outcomes, or durability after treatment. Although the registry names percent change from baseline of other lipids as a secondary outcome, numerical results for that outcome are not reported in the registry record.

7. Results Posted in the Registry

• Atorvastatin 20 mg: mean -42.00 versus 2.00 on control; difference -44.00 (95% CI -51.89 to -36.11), standardized effect d = -3.15; z-test p = <0.001.
• AEGR-733 5 mg: mean -16.00 versus 2.00 on control; difference -18.00 (95% CI -27.12 to -8.88), standardized effect d = -1.28; z-test p = <0.001.
• AEGR-733 10 mg: mean -37.00 versus 2.00 on control; difference -39.00 (95% CI -53.92 to -24.08), standardized effect d = -2.54; z-test p = <0.001.
• AEGR-733 5 mg + Atorvastatin 20 mg: mean -47.00 versus 2.00 on control; difference -49.00 (95% CI -58.90 to -39.10), standardized effect d = -3.26; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous and summarized by a mean and standard deviation. General statistical explanation: a mean is the arithmetic average of observations in a group. A standard deviation describes how spread out observations are around that average. It is not a confidence interval and does not mean that all individual observations lie within a fixed distance of the mean. The registry provides both summaries for each arm in the primary outcome population.

What does the mean difference represent?

The reported mean difference compares an active group’s average percent change with the placebo group’s average percent change. For example, the posted difference for atorvastatin 20 mg is -44.0, with the placebo mean listed as 2.0 and the atorvastatin mean listed as -42.0. The estimate’s negative sign reflects the direction of the active-group mean relative to the control mean. This contrast is about average change; it does not describe the distribution of each participant’s response or establish that the same change occurred for everyone.

The four posted differences are recalculated, simple unadjusted contrasts from the arm-level summaries. The calculations use the listed group means and standard deviations, with a pooled standard deviation also reported for each comparison. A pooled standard deviation combines within-group variability for the purpose of a two-group comparison. The recalculations are not evidence of a sponsor-reported adjusted model. The registry record reports zero analysis entries, and it does not describe a statistical model, covariate adjustment, or a prespecified analysis plan.

How should the p-values be read?

General statistical explanation: a p-value evaluates how unusual a result at least as different as the observed result would be under a specified null model. It is not the probability that the null hypothesis is true, and it does not measure the magnitude or importance of an observed difference. The unadjusted p-values for all four posted comparisons are <0.001. They should be read as results for those particular unadjusted contrasts, not as a global test of all six arms. The registry record does not report adjustment for multiple comparisons.

There are several active groups, and placebo is reused as the control in the reported contrasts. When many hypotheses are tested, the chance of at least one apparently unusual result can increase. General methods for addressing this include prespecifying a primary contrast or adjusting the testing procedure, but which approach, if any, was part of the trial’s own plan is not reported in the registry record. The posted p-values therefore remain unadjusted and should not be treated as multiplicity-controlled results.

What information does a confidence interval add?

General statistical explanation: a confidence interval describes a range of estimates compatible with the data and the interval procedure under its assumptions. It communicates uncertainty around an estimate, whereas a p-value gives a different summary tied to a null hypothesis. The confidence intervals posted for the four comparisons do not include zero. However, the confidence level and exact interval procedure are not reported in the registry record. The interval limits should therefore be read as posted, without assuming additional details about their construction.

The intervals and p-values are based on recalculated comparisons, not on a reported sponsor analysis. The record does not list degrees of freedom, a model specification, or a method for handling departures from distributional assumptions. General statistical explanation: a normal approximation is often used to obtain simple comparisons of means, but its accuracy can depend on the outcome distribution and sample size. The sample-size illustration explicitly states a normal approximation; that planning assumption should not be mistaken for a description of the trial’s original analysis.

What does the Intent To Treat label tell us?

The primary outcome is labeled Intent To Treat, which identifies the named analysis population. The registry record does not specify how missing endpoint values were handled, whether every randomized participant contributed an observed endpoint, or whether any imputation was used. It also does not provide a participant flow account that would explain differences between enrollment, endpoint arm counts, and safety denominators. No assumptions about the causes of these differences or the handling of incomplete data can be inferred from the posted summaries.

The primary time point is after 8 weeks on study drug. Results at this time point are not a longitudinal trajectory. The record does not describe interim analyses, stopping rules, or whether the reported time point was selected after examining results. Those elements of the statistical plan are not reported in the registry record. As a result, the appropriate interpretation stays close to the quantities that are posted: arm means and standard deviations, four unadjusted mean differences, confidence intervals, and p-values.

10. Confidence Intervals and Precision

The posted confidence intervals quantify uncertainty around four recalculated mean differences. For atorvastatin 20 mg versus placebo, the estimate is -44.0 and the interval runs from -51.89 to -36.11. For AEGR-733 5 mg versus placebo, the estimate is -18.0 and the interval runs from -27.12 to -8.881. For AEGR-733 10 mg versus placebo, the estimate is -39.0 and the interval runs from -53.92 to -24.08. For AEGR-733 5 mg plus atorvastatin 20 mg versus placebo, the estimate is -49.0 and the interval runs from -58.9 to -39.1.

General statistical explanation: an interval gives a range of plausible values for the contrast under the assumptions of the calculation. A narrower interval indicates greater precision than a wider interval, while an interval’s location indicates the direction and scale of the estimated contrast. Precision is influenced by within-group variability and the amount of information available. The posted arm counts and standard deviations differ, so the comparisons do not all have the same information base.

All four posted intervals lie on the negative side of zero, consistent with their negative point estimates. This describes the recalculated contrasts and does not determine clinical importance. The confidence level and exact interval method are not reported in the registry record. There is also no posted interval for the AEGR-733 10 mg plus atorvastatin 20 mg comparison with placebo. Its arm summary alone does not supply the uncertainty around a contrast.

The intervals are unadjusted for the set of multiple active-versus-placebo comparisons. A reader should not interpret them as if the record documented a family-wise or other multiplicity procedure. Their precision also concerns the mean contrast at the stated endpoint and time point, not individual outcomes, longer-term effects, or unreported endpoints.

11. 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, not total event counts. They are illustrations computed from the observed effect, rather than the trial’s original design assumptions; those original assumptions are not reported in the registry record. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning row uses the stated fraction of the observed effect as the effect to detect.

The columns for 80% power and 90% power describe the number of participants per arm used in a hypothetical design to have the stated chance of detecting the assumed effect at the specified significance level, if the planning assumptions hold. Higher target power generally calls for more information. The rows labeled 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect represent progressively smaller effects to detect. Smaller effects need more participants, all else equal.

For example, the planning figures for AEGR-733 5 mg versus placebo are 10 participants per arm for 80% power and 13 participants per arm for 90% power when planning for 100% of the observed effect. For 50% of the observed effect, the figures are 39 and 52 participants per arm, respectively. These are planning illustrations, not enrollment recommendations or evidence about the study’s actual design process. They are not observed power; observed power is not an appropriate retrospective measure of how convincing a result is.

The displayed comparisons have separate planning figures, so the numbers should be read in the context of the corresponding contrast and assumed effect fraction. They do not provide a sample-size illustration for the AEGR-733 10 mg plus atorvastatin 20 mg versus placebo comparison, because that recalculated contrast is not posted.

12. 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 = -44.000; pooled standard deviation σ = 13.988.
2. n = 2 × (1.96 + 0.842)² × 13.988² / -44.000² = 1.6, rounded up to 2 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 <- -44                      # observed difference in means
sigma <- 13.9883233980832                     # 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(474240)
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 = 2 (80% power), 3 (90% power)
 75% of observed effect: n per arm = 3 (80% power), 4 (90% power)
 50% of observed effect: n per arm = 7 (80% power), 9 (90% power)
power.t.test: 2.9 
Simulated power at n = 2 per arm: 0.419 (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.

13. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is identified, and four unadjusted recalculations compare active groups with placebo. The registry record does not report a multiplicity procedure, such as a correction to the significance threshold or an ordered testing strategy. Because several comparisons use the same control group, the posted p-values should be treated as unadjusted evidence for individual contrasts rather than as a set of multiplicity-controlled tests. The record also does not state whether these four contrasts were prespecified as the principal comparisons.

The primary outcome population is labeled Intent To Treat. That label does not, by itself, explain how missing measurements were addressed. The registry record does not report the amount or pattern of missing endpoint data, an imputation approach, a complete-case strategy, or sensitivity analyses. It also does not provide a participant disposition that reconciles the enrollment number with the arm-specific endpoint and safety counts. Those omissions prevent assessment of whether missingness could have affected the estimates.

The primary endpoint is a continuous measure, summarized by means and standard deviations. The registry record does not report a sponsor analysis model, covariate adjustment, model diagnostics, or a formal method for handling unusual distributions. The posted comparisons are simple unadjusted recalculations, and no discrepancy is flagged. No inferential comparison is posted for AEGR-733 10 mg plus atorvastatin 20 mg against placebo.

One secondary outcome is named: percent change from baseline of other lipids. Numerical results for that outcome are not reported in the registry record. The record’s analysis listing contains zero analyses. Protocol details on interim analyses, multiplicity planning, missing-data handling, and analysis-population implementation are not reported in the registry record. These gaps mean that the posted summary supports a limited reading of the available endpoint statistics but cannot establish how all planned analyses were conducted.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial infarction (3.8%).

The serious adverse-event results are reported as affected participants among those at risk in each safety group. Placebo had 0 affected among 27 at risk; atorvastatin 20 mg had 0 among 26; AEGR-733 5 mg had 1 among 26; AEGR-733 10 mg had 1 among 26; AEGR-733 5 mg plus atorvastatin 20 mg had 0 among 26; and AEGR-733 10 mg plus atorvastatin 20 mg had 0 among 26. These are group-specific counts, not rates calculated for comparison in this discussion.

The registry lists myocardial infarction at 3.8% among the top serious adverse-event terms. It does not identify the treatment group associated with that term in the record. Deaths are not reported in the registry record. For other adverse events, the reported affected counts are 17 of 27 for placebo, 15 of 26 for atorvastatin 20 mg, 23 of 26 for AEGR-733 5 mg, 23 of 26 for AEGR-733 10 mg, 21 of 26 for AEGR-733 5 mg plus atorvastatin 20 mg, and 24 of 26 for AEGR-733 10 mg plus atorvastatin 20 mg. These counts should be read as registry summaries, not as a complete account of event types, severity, timing, or causality.

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

The primary endpoint results describe average percent change in LDL-C after 8 weeks on study drug among the named Intent To Treat population. The posted arm means range from a placebo mean of 2.0 to active-group means of -16.0, -37.0, -42.0, -47.0, and -50.0. These values are descriptive averages, and their standard deviations show that observations varied within each group. The four recalculated active-versus-placebo mean differences are negative, with unadjusted p-values of <0.001 and posted intervals that do not include zero.

Those results do not establish that every participant experienced a change like the group average. Nor do they show whether an observed difference is clinically important; the registry record does not report a threshold for clinical importance. Statistical evidence against a no-difference null is not a direct measure of benefit, and the unadjusted p-values do not address the multiplicity of comparisons. No treatment recommendation follows from these statistics.

The results are limited to the stated endpoint and time point. They do not report long-term lipid changes, cardiovascular outcomes, persistence after stopping study drug, or detailed safety outcomes by event type. The record does not provide a recalculated placebo contrast for AEGR-733 10 mg plus atorvastatin 20 mg. Although a mean and standard deviation are posted for that arm, a contrast with uncertainty cannot be inferred from the arm summary alone.

Finally, the registry record does not report the confidence level for the posted intervals, the original analysis plan, missing-data methods, or multiplicity handling. These limits do not erase the descriptive pattern in the posted summaries, but they constrain what can be concluded from it. The statistics speak to group averages in this trial’s registry results, not to all populations or outcomes.

16. Why This Trial Matters Statistically

This trial presents a useful statistical contrast between a continuous endpoint and a multi-arm design. The primary result is not simply a count of participants with a favorable or unfavorable outcome; it is the mean percent change in LDL-C, accompanied by standard deviations that describe within-group variability. That distinction matters because averages can differ even when individual responses vary widely, and arm-level means do not reveal the full distribution of participant outcomes.

The design includes placebo, atorvastatin alone, AEGR-733 alone at two doses, and two combination groups. This makes clear why a result must be tied to the precise comparison being discussed. The posted recalculations cover four active-versus-placebo contrasts, not every possible pair of arms. In particular, the combination group using AEGR-733 10 mg has an arm summary but no posted unadjusted contrast against placebo. Distinguishing an arm description from an inferential comparison prevents overreading a result that is not reported.

The record also illustrates the difference between a trial’s observed data and a planning exercise. The planning figures are based on fractions of observed effects under stated assumptions; they are not evidence of the original design rationale or of the study’s achieved power. Likewise, p-values and confidence intervals answer related but distinct questions, and neither alone establishes clinical importance.

Finally, safety summaries and endpoint summaries use different reported group counts. A careful reading keeps those denominators attached to their own outcome rather than treating them as interchangeable. The registry’s incomplete reporting of multiplicity, missing-data handling, interval construction, and analysis plans further shows why statistical interpretation depends not only on estimates, but also on methods and reporting context.

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 primary endpoint is reported at one time point, after 8 weeks on study drug. Results at later times and the persistence of any change are not reported in the registry record. Although the registry names percent change from baseline of other lipids as a secondary outcome, its numerical results are not reported in the registry record. The primary endpoint summaries therefore do not describe all lipid outcomes named for the study.

The posted primary arm counts differ from the safety denominators, and the record does not provide participant flow or explain those counts. The Intent To Treat label is present, but missing-data methods and the handling of participants without an observed endpoint are not reported in the registry record. This limits assessment of the potential effect of incomplete outcome data.

The four mean differences are recalculated, unadjusted comparisons, and there is no posted contrast for AEGR-733 10 mg plus atorvastatin 20 mg versus placebo. No multiplicity correction, sponsor-reported analysis model, confidence level, or exact interval procedure is reported in the registry record. The record also does not report the original sample-size justification, interim analyses, or a detailed statistical plan. Consequently, the planning figures should not be read as the trial’s design rationale.

Safety reporting is limited in the registry record: death counts are not reported in the registry record, and the listed serious term myocardial infarction is not assigned to a specific group. Detailed event descriptions, timing, severity, and attribution are not provided in the registry record. Participant demographics beyond the condition and detailed treatment adherence information are also not reported in the registry record. These limits narrow the interpretation to the posted summaries.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: AEGR-733 and Atorvastatin 20 mg vs. Monotherapy in Moderate Hypercholesterolemia — NCT00474240.
• Registry record last updated 2018-03-20; status last verified 2013-01.
• Results first posted 2013-02-21.
• 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

NCT00474240 is a completed randomized, triple-masked, parallel-group phase 2 study sponsored by Aegerion Pharmaceuticals, Inc. It enrolled participants with moderate hypercholesterolemia and investigated AEGR-733, atorvastatin 20 mg, and their combinations, with placebo and atorvastatin-alone groups also listed. The registry gives a start of 2007-04 and primary completion of 2008-10.

The primary endpoint was mean percent change from baseline in LDL-C at 8 weeks on study drug in an Intent To Treat population. The posted arm summaries include means and standard deviations for six groups. Four unadjusted recalculations compare active groups with placebo, each with a p-value of <0.001. A recalculated comparison for AEGR-733 10 mg plus atorvastatin 20 mg versus placebo is not reported in the registry record. Missing-data methods, multiplicity handling, and the trial’s original sample-size assumptions are not reported in the registry record.