24 Months Follow-up, Two Arm Study to Compare the Cardiovascular Profile in a Regimen With Everolimus + Mycophenolic Acid (MPA) Versus (vs.) a Regimen of CNI+MPA in Maintenance Renal Transplant Recipients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for 24 Months Follow-up, Two Arm Study to Compare the Cardiovascular Profile in a Regimen With Everolimus + Mycophenolic Acid (MPA) Versus (vs.) a Regimen of CNI+MPA in Maintenance Renal Transplant Recipients (NCT01169701), a randomized phase 4 study. The primary outcome is Change From Baseline in Left Ventricular Mass Index (LVMI).

2. Clinical Question

The study’s stated objective was to compare the cardiovascular profile of an everolimus-and-MPA regimen with a calcineurin-inhibitor-and-MPA regimen in maintenance renal transplant recipients. Left ventricular mass index was the primary outcome, while the registry also lists cardiovascular, renal-function, and biomarker outcomes. The primary result therefore addresses one specified measure of cardiovascular structure over the stated follow-up, rather than the entire range of cardiovascular outcomes or overall clinical benefit.

The study was randomized and open-label. Randomization is intended to create comparable groups on average, while open-label means the registry does not describe masking of participants or study personnel. The record does not report whether outcome assessment was blinded. These design features help frame the comparison but do not by themselves establish that the groups were identical at baseline or that every difference in follow-up was caused by treatment assignment.

3. Trial Design

The registry describes a multicenter, randomized, open-label, parallel, two-arm Phase 4 study with 24 months of follow-up. It concerns maintenance renal transplant recipients and compares an everolimus regimen with a tacrolimus regimen, both involving mycophenolic acid. The study status is completed. The registry lists enrollment as 71, with a start date of 2010-08 and primary completion in 2014-03.

In the tacrolimus arm, participants continued the same tacrolimus-plus-MPA doses they had used before study initiation; the record describes tacrolimus levels of 4-7 ng/ml. The everolimus arm description includes an initial dose of everolimus 2mg at night and changes to tacrolimus dosing during the first days, followed by everolimus 2 mg twice daily on days 2 and 3. The registry lists everolimus, tacrolimus, and MPA as study drugs. These descriptions do not provide a complete account of all treatment adjustments or the full regimen over the entire follow-up period.

The primary outcome results use 31 participants in the tacrolimus group and 25 in the everolimus group. The safety summaries use 36 participants at risk in each group for their respective arm records: 36 for tacrolimus and 35 for everolimus. These counts refer to different posted summaries and should not be treated as interchangeable. The registry does not report reasons for differences between these analysis counts and enrollment, or reasons participants may not have contributed to the primary outcome analysis.

The record lists 14 outcome measures and 13 posted secondary outcomes. These include blood pressure, pulse wave velocity, major cardiovascular events, renal-function measures, and cardiovascular biomarkers. The registry’s analysis-count field is zero; it does not provide further detail about the statistical analyses underlying the posted primary result. The original sample-size justification, detailed analysis plan, and any interim-analysis plan 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants from the Intent to Treat (ITT) analysis set, who had both baseline and month 24 values, were analyzed. The ITT included participants who received at least one dose of study medication and at least one post baseline LVMI value.

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 Change From Baseline in Left Ventricular Mass Index (LVMI), measured over Baseline, Month 24.

The primary endpoint is change from baseline in left ventricular mass index (LVMI), measured in g/m^2.7. The registry says LVMI was calculated from an echocardiogram and assessed at baseline and Month 24. Left ventricular mass is a measure of the heart’s structural mass, and indexing it to body size is intended to make measurements more comparable across people. The record defines left ventricular hypertrophy using sex-specific LVMI thresholds: > 49.2 g/m^2.7 in men and >46.7 g/m^2.7 in women.

The outcome is reported as a mean change, with standard deviation describing variation among participants in each group. A negative change from baseline is identified in the registry as improvement. This sign convention matters when interpreting the group means: a more negative mean indicates a larger average reduction in LVMI, while the between-group difference expresses how the two average changes compare.

LVMI is used as a cardiovascular structural measure, consistent with the study’s stated interest in cardiovascular profile. It is one outcome and does not by itself describe blood pressure, cardiovascular events, renal function, biomarkers, or participants’ overall health. The record’s primary analysis included participants from the Intent to Treat set who had both baseline and Month 24 LVMI values. The registry does not report further details on echocardiogram reading procedures or whether assessors were masked to treatment assignment.

7. Results Posted in the Registry

• Everolimus: mean -4.01 versus -6.07 on control; difference 2.06 (95% CI -7.83 to 11.95), standardized effect d = 0.11; z-test p = 0.683.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant has a numerical LVMI change, and the registry reports the mean change for each group. For this type of outcome, a group mean describes the average observed change, while a standard deviation describes how dispersed participant values are around that average. The mean is useful for summarizing the group but does not imply that all participants had changes close to it. General statistical context: when individual outcomes vary widely, estimates of group averages can be less precise, especially when the number of observations is limited.

What does the mean difference represent?

The reported contrast is the everolimus-group mean change minus the tacrolimus-group mean change. The group means are -4.008 and -6.071 g/m^2.7, respectively, and the estimated difference is 2.063 g/m^2.7. Because the registry defines a negative change as improvement, the sign of the contrast is interpreted against that convention. A positive difference means the everolimus group’s mean change was less negative. This is a comparison of averages, not a claim about each participant or an estimate of the probability that an individual will experience a particular result.

A standard deviation and a standard error describe different things. The standard deviations reported for the arms, 17.61 and 20.12 g/m^2.7, describe dispersion among participant changes. The standard errors reported for the arm means, 3.522 and 3.613, describe uncertainty in the estimated group means. General statistical context: standard errors tend to be smaller when observations are less variable or when more observations contribute, but they are not measures of the spread of individual outcomes. The standard error of a mean difference is used in constructing an inferential comparison, though the registry record does not provide a full account of the calculation or model.

How should the confidence interval be read?

The 95% confidence interval for the mean difference is -7.826 to 11.95 g/m^2.7. In general, a confidence interval is a range of values compatible with the observed data under the statistical procedure used. Its width conveys precision: a narrower interval indicates more precision than a wider one, all else equal. This interval includes zero and also includes values on either side of zero. It therefore does not isolate a single direction or a narrow range of possible differences. A confidence interval is not a statement that there is a 95% probability that the fixed treatment effect lies inside this particular interval.

What does the p-value add?

The unadjusted p-value is 0.683. General statistical context: a p-value measures how unusual data at least as incompatible with a null hypothesis would be if that null hypothesis and the analysis assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. Here it is described as unadjusted; the registry does not report whether or how any multiplicity adjustment was applied to the broader set of outcomes. The p-value should be read alongside the effect estimate and confidence interval rather than as a stand-alone decision about the result.

What is a standardized effect?

The record also gives a standardized effect size of 0.108 and a pooled standard deviation of 19.04. A standardized effect expresses the estimated difference in relation to a measure of outcome variability, placing the contrast on a scale that is not tied to the original LVMI units. General statistical context: standardization can make effect magnitudes easier to compare across measures, but it does not replace the original-unit estimate, which is more directly interpretable for this endpoint. The standardized value does not eliminate uncertainty in the estimate.

The primary population definition is important to the method. Participants had to be in the stated Intent to Treat set and have both baseline and Month 24 LVMI values. This is a measurement-complete subset of that defined set for the primary endpoint. General statistical context: complete-measurement analyses can be affected if the availability of outcome data is related to participant characteristics or outcomes. The registry does not report the reasons for missing measurements, a missing-data method, or sensitivity analyses, so the extent of any such effect cannot be determined from the record.

The study is described as randomized, open-label, parallel, and multicenter. Randomization is a design method intended to balance known and unknown baseline factors across groups on average. Open-label status means the record reports no masking; it does not state whether echocardiogram readers or other outcome assessors were masked. General statistical context: randomization supports a comparison based on assigned groups, while masking can help limit some forms of measurement or behavioral bias. Neither feature guarantees that all sources of bias are absent.

Finally, any interpretation should distinguish the posted results from a complete statistical analysis plan. The record gives the group summaries, a contrast, an interval, and an unadjusted p-value, but does not report a detailed model specification, covariate adjustment, assessment of distributional assumptions, or prespecified handling of multiple outcomes. Those features are not inferred from the numerical results. The explanations of means, intervals, standard errors, and p-values above are general statistical context; the reported estimates remain the registry’s specific result for LVMI change.

10. Confidence Intervals and Precision

The estimated mean difference is 2.063 g/m^2.7, with a 95% confidence interval from -7.826 to 11.95 g/m^2.7. The interval is wide relative to the point estimate and spans both negative and positive values. This signals that the data do not pinpoint the direction or size of the average difference with much precision. Values near zero are compatible with the interval, as are differences in either direction across a broader range.

Precision depends on the amount of information in the analysis and on variability in the outcome. The primary endpoint summary includes 31 participants in the tacrolimus group and 25 in the everolimus group. The reported standard deviations are 20.12 and 17.61 g/m^2.7. General statistical context: higher variability and fewer observations can make a group comparison less precise, although the registry record does not give a formal breakdown of how each factor contributed to this interval.

The confidence interval should be considered together with the unadjusted p-value of 0.683. Neither statistic establishes equivalence or rules out a difference. The interval describes statistical uncertainty around the estimated contrast under the analysis procedure, but the record does not report enough detail to assess every assumption or the effects of missing endpoint values. Nor does the interval answer whether any particular difference would be clinically important; the registry does not state a threshold for a clinically important LVMI change.

Precision is not the same as correctness. A narrow interval would indicate greater statistical precision under the method, but would not by itself rule out bias or limitations in the population analyzed. In this study, the open-label design, the endpoint-complete population, and the lack of reported details about missing-data handling and outcome-assessment masking are relevant context for interpreting what the interval can establish.

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 sample-size figures are planning illustrations based on the observed effect, not the trial’s original design justification. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect targeted in each scenario is the stated fraction of the observed effect: the full observed effect, 75% of the observed effect, or 50% of the observed effect. The resulting figures are participants per arm for 80% power and participants per arm for 90% power. They are not total participants across both arms and are not total event counts.

The 80% power column describes the illustrative number of participants per arm needed under those assumptions for an analysis to have an 80% chance of detecting the specified effect if that effect is the true one and the assumptions hold. The 90% power column expresses the corresponding planning target at 90% power. In general, higher power requires more participants when the other assumptions are unchanged. The figures are not a forecast of what a future study will achieve, because actual precision and power depend on the true effect, variability, data completeness, and analysis choices.

Smaller target effects require more participants to distinguish them from random variation. Accordingly, planning for 75% or 50% of the observed effect gives larger participant requirements than planning for the full observed effect. The observed effect in this study is small relative to the reported outcome variability, so the illustrative requirements are large. These calculations are based on the observed result and should not be mistaken for a prospective justification used to design this trial. They are not observed power. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

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 = 2.063; pooled standard deviation σ = 19.043.
2. n = 2 × (1.96 + 0.842)² × 19.043² / 2.063² = 1,337.5, rounded up to 1,338 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 <- 2.063                      # observed difference in means
sigma <- 19.0429796921479                     # 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(1169701)
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 = 1,338 (80% power), 1,791 (90% power)
 75% of observed effect: n per arm = 2,378 (80% power), 3,184 (90% power)
 50% of observed effect: n per arm = 5,351 (80% power), 7,163 (90% power)
power.t.test: 1338.5 
Simulated power at n = 1,338 per arm: 0.807 (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 registry lists 14 outcome measures and 13 posted secondary outcomes, in addition to the primary LVMI outcome. The secondary measures span blood pressure, pulse wave velocity, major cardiovascular events, renal function, and biomarkers. When several outcomes are tested, the chance of at least one apparently notable result can rise if each is assessed separately without adjustment. General statistical context: multiplicity methods can control or otherwise address this issue, but they may change the interpretation of individual p-values and confidence intervals.

The primary comparison is reported with an unadjusted p-value of 0.683. The registry record does not report a multiplicity procedure, a hierarchy among outcomes, or which outcomes were designated for formal hypothesis testing. It is therefore not possible to determine from the record whether the posted result is part of a broader adjusted testing strategy. The unadjusted p-value should not be treated as evidence that all outcome comparisons were controlled for multiple testing.

For the primary analysis population, the record says participants had to be in the Intent to Treat set, receive at least one dose, have at least one post-baseline LVMI value, and have both baseline and Month 24 values for the endpoint analysis. This definition makes clear that the reported mean-change summaries are based on participants with the required measurements. The registry does not report how many participants lacked those measurements, why data were missing, or whether a model or imputation approach was used for missing values. It also does not report sensitivity analyses examining alternative assumptions about missingness.

The original statistical analysis plan, detailed covariate adjustment, interim-analysis plan, and sample-size justification are not reported in the registry record. These omissions limit assessment of prespecification and of how the posted estimates relate to the complete intended analysis strategy. The registry’s analysis-count field is zero, but that field alone does not explain the methods used to generate the posted result. No unreported method should be inferred from the mean difference, confidence interval, or p-value.

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: drug hypersensitivity (2.9%), oral herpes (2.9%), pneumonia (2.9%), respiratory syncytial virus infection (2.9%), septic shock (2.9%).

The serious adverse event summaries list 36 participants at risk and 5 affected in the tacrolimus group, and 35 participants at risk and 8 affected in the everolimus group. These are the counts recorded for the safety summaries. They should be read as group-specific records, not as direct measures of treatment causality. The registry does not provide a comparison estimate or statistical test for these figures.

The listed serious adverse event terms are Drug hypersensitivity, Oral herpes, Pneumonia, Respiratory syncytial virus infection, Septic shock, and Urosepsis, each reported as 2.9%. These term-level percentages should not be added together: the record does not establish that the terms represent mutually exclusive participants. The summary also lists other adverse events affecting 21 participants in the tacrolimus group and 24 in the everolimus group.

Deaths are not reported in the registry record. The safety figures do not establish that an event was caused by a study regimen, and they do not by themselves allow a complete comparison of risks. Differences in the number of participants represented, follow-up, event definitions, or ascertainment can matter; details addressing these issues are not reported in the registry record.

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

The posted primary outcome is the average change in LVMI from baseline to Month 24 among participants meeting the registry’s endpoint-analysis criteria. The means were negative in both groups, and the registry defines a negative change as improvement. The estimated difference between the group means was 2.063 g/m^2.7, with a 95% confidence interval from -7.826 to 11.95 g/m^2.7. The interval includes zero and allows differences in either direction, so the result is not a precise determination of which group had the larger average reduction.

This finding does not demonstrate that the regimens are equivalent, nor does it show that their true average effects are identical. A result with a confidence interval that includes zero may still be compatible with potentially meaningful differences in either direction, depending on what differences matter clinically. The registry does not report a threshold for clinical importance, so the clinical meaning of particular values within the interval cannot be established from this record alone.

The endpoint is LVMI, one measure of cardiovascular structure. It is not a direct summary of cardiovascular events, blood pressure, renal function, or overall health. Although the registry lists those and other secondary outcomes, the primary result cannot be used to infer their results. Nor does an average group change indicate what happened to a specific participant.

The study was randomized but open-label, and the endpoint analysis required baseline and Month 24 measurements. The record does not report whether outcome assessors were masked or how missing measurements were handled. These limitations affect the context in which the estimate should be interpreted. The statistical result describes the posted comparison; it is not medical advice and does not establish whether an individual should receive either regimen.

16. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between an estimated contrast and the certainty around that contrast. The mean changes were -6.071 g/m^2.7 in the tacrolimus group and -4.008 g/m^2.7 in the everolimus group, while the between-group estimate was 2.063 g/m^2.7. Reading the point estimate alone could suggest a particular direction, but the 95% confidence interval from -7.826 to 11.95 g/m^2.7 shows substantial uncertainty and includes differences in either direction.

The example also highlights why a non-small p-value is not evidence of equivalence. The unadjusted p-value is 0.683, but the interval does not tightly constrain the range of plausible group differences. A study can therefore have an estimated difference that is not statistically compelling while still leaving uncertainty about the size and direction of the true difference. Equivalence requires a prespecified margin and an analysis designed to assess it; such a margin or analysis is not reported in the registry record.

Variation among individual changes matters as well. The reported standard deviations, 20.12 and 17.61 g/m^2.7, are large compared with the estimated group contrast. This makes the distinction between a group average and individual outcomes especially important. The sample-size illustrations further show, in general, that targeting smaller effects requires more participants under fixed planning assumptions. Those illustrations are not a substitute for the original design justification, which is not reported.

Finally, interpretation depends on knowing who contributed data and how analysis decisions were made. The primary endpoint used participants with both baseline and Month 24 values, while the registry does not explain missing measurements, multiplicity handling, or the detailed statistical plan. These are central considerations when judging what a numerical result can support.

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 analysis includes participants with both baseline and Month 24 LVMI values rather than every participant listed under enrollment. The registry gives the endpoint population definition but does not report the number or characteristics of participants without the required values, their reasons for missing data, or how missingness was handled. If data availability is related to participant characteristics or outcomes, a complete-measurement analysis may not fully represent all randomized participants; the record does not allow that possibility to be assessed.

The study was open-label. The registry does not report whether echocardiogram assessors were masked to treatment assignment, or provide detailed procedures for measurement quality control. Because the primary endpoint is based on echocardiography, the absence of these details limits evaluation of possible measurement-related bias. This is a limitation in the reported information, not evidence that measurement bias occurred.

The record does not report the original sample-size justification, a detailed statistical analysis plan, multiplicity procedures, covariate adjustments, or interim analyses. It also does not state a clinically important difference for LVMI. These gaps make it difficult to assess whether the posted analysis follows prespecified decisions or how the estimate relates to a threshold that would matter clinically.

The registry lists 71 participants for enrollment, but the primary endpoint and safety summaries use their own analysis counts. Reasons for the differences among these counts are not reported. The safety record also does not report deaths, and the adverse-event summaries alone do not establish causal relationships or provide a formal treatment comparison. Finally, the reported primary endpoint concerns LVMI change, so it cannot substitute for results on the other listed cardiovascular, renal, and biomarker outcomes.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: 24 Months Follow-up, Two Arm Study to Compare the Cardiovascular Profile in a Regimen With Everolimus + Mycophenolic Acid (MPA) Versus (vs.) a Regimen of CNI+MPA in Maintenance Renal Transplant Recipients — NCT01169701.
• Registry record last updated 2015-12-07; status last verified 2015-11.
• Results first posted 2015-04-30.
• 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

NCT01169701 is a completed, randomized, open-label, multicenter, parallel, two-arm Phase 4 study in maintenance renal transplant recipients. It compared an everolimus-and-MPA regimen with a tacrolimus-and-MPA regimen over 24 months. The registry lists enrollment of 71 and primary completion in 2014-03.

The primary outcome was mean change from baseline to Month 24 in LVMI. The mean changes were -6.071 g/m^2.7 for tacrolimus and -4.008 g/m^2.7 for everolimus; the estimated between-group difference was 2.063 g/m^2.7, with a 95% confidence interval from -7.826 to 11.95 and an unadjusted p-value of 0.683. The registry defines negative change as improvement.

The record lists cardiovascular, renal, and biomarker secondary outcomes and includes serious and other adverse-event summaries. Detailed missing-data procedures, multiplicity methods, the original sample-size justification, and the full statistical analysis plan are not reported in the registry record.