Study Evaluating Sirolimus in Kidney Transplant Recipients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Evaluating Sirolimus in Kidney Transplant Recipients (NCT00195273), a randomized phase 3 study. The primary outcome is Mean Creatinine Clearance Rate.

2. Clinical Question

The trial addresses a comparison of two multi-drug regimens, rather than the isolated effect of one medicine. The intervention group included daclizumab, which was not listed in the comparator regimen, while both groups included mycophenolate and corticosteroids. Thus, the group contrast concerns the complete regimens described in the registry record.

The primary outcome is a continuous measure, reported as a mean in ml/min. The record also lists secondary questions about acute rejection, patient and graft survival, and creatinine clearance at 3 months. The registry record does not report enough detail to determine whether the study was designed to establish equivalence or noninferiority; its primary comparison is described as superiority or other.

3. Trial Design

The registry record describes a randomized, open-label, parallel-group Phase 3 study. Participants were assigned to either the sirolimus regimen with daclizumab, mycophenolate and corticosteroids, or the cyclosporine regimen with mycophenolate and corticosteroids. Masking is listed as none, so the record does not describe blinded treatment assignment or assessment.

Enrollment is listed as 61. The primary outcome is the mean creatinine clearance rate at 12 months, measured among patients who completed 12 months of study drug. The posted outcome summaries include 20 participants in each group. The registry record does not explain the relationship between the enrollment figure and the endpoint population counts, or give a participant flow accounting for exclusions, withdrawals or missing measurements.

The record lists study start as 2004-11 and primary completion as 2008-07, with status completed. It names kidney transplantation among the conditions and describes recipients of kidneys from older donors in the official study title. Additional inclusion and exclusion criteria, treatment doses, treatment duration beyond the endpoint wording, and details of follow-up are not reported in the registry record.

Random allocation can support a comparison of groups by assigned regimen, but the registry record does not establish which analysis population or statistical handling of missing outcomes was used for the sponsor's analysis. Open-label conduct means treatment assignment was not masked, although the record does not say whether outcome measurement or analysis was masked. The registry record also does not report the original sample-size justification or the trial's detailed statistical analysis plan.

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: Prior to enrollment in study, patients were screened for eligibility. If eligibility criteria were met, patients were enrolled and randomized.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients who completed 12 months of study drug.

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 Mean Creatinine Clearance Rate, measured over 12 months.

Mean creatinine clearance rate at 12 months is the primary endpoint. Creatinine clearance estimates the volume of blood plasma cleared of creatinine by the kidneys per unit time. The registry record states that it was calculated using the Nankivell formula. The measure is expressed in ml/min, and lower clearance is described in the record as indicating poorer kidney function.

A continuous endpoint preserves variation across measured values and allows comparison of group means. The registry record describes healthy reference ranges, but those ranges do not by themselves define a clinical threshold for the trial population or establish how a particular group difference should be interpreted. The primary question is the difference between the two assigned regimens at the specified time point, not whether either group's mean falls within a healthy reference range.

The outcome population is specifically patients who completed 12 months of study drug. This definition matters: the endpoint summaries describe that completion-based group, not necessarily everyone randomized. The registry record does not report how many randomized participants had unavailable measurements or why, and does not describe whether the formula-based estimates were supplemented by direct measurements.

7. Results Posted in the Registry

• Cyclosporine (CsA): mean 53.45 versus 56.80 on control; difference -3.35 (95% CI -14.97 to 8.27), standardized effect d = -0.18; z-test p = 0.572.

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.

Mean Creatinine Clearance Rate - 3 Months

• 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:
  • Cyclosporine (CsA): mean 51.88 versus 55.20 on control; difference -3.32 (95% CI -13.70 to 7.06), standardized effect d = -0.17; z-test p = 0.530.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cyclosporine (CsA) and the control. The interval gives the range of effects that remain compatible with the data.

The registry record names acute rejection, patient and graft survival, and 3-month creatinine clearance as secondary outcomes. Numerical results are posted for the 3-month mean creatinine-clearance comparison, but the record does not report numerical results for the other named secondary outcomes. The 3-month comparison's estimated direction is consistent with the primary estimate, and its confidence interval includes zero. Taken together, the two time-point estimates do not provide clear evidence of a mean difference, while both remain uncertain.

The secondary findings should be read alongside, not as a replacement for, the primary result. The primary endpoint is the 12-month measure specified as the main outcome; an additional time point can provide context about the pattern over time, but it does not resolve the uncertainty in the primary comparison. Nor can results for creatinine clearance answer questions about rejection or survival.

Secondary analyses generally carry less weight when their prespecification, testing hierarchy and multiplicity handling are unclear. Testing several outcomes or time points can increase the chance of a seemingly notable result arising by chance. The registry record does not report a multiplicity adjustment or enough detail to determine how these secondary outcomes were prioritized. For that reason, individual secondary p-values should not be treated as confirmatory evidence without the analysis plan and full results.

The record lists three secondary outcomes but the available numerical secondary results include only the 3-month creatinine-clearance measure. Results, analysis populations and missing-data handling for the other named outcomes are not reported in the registry record. That incomplete reporting prevents a balanced assessment of the full secondary outcome set.

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

• Number of Patients With Acute Rejection
• Patient and Graft Survival
• Mean Creatinine Clearance Rate - 3 Months

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the registry record reports a mean and standard deviation for each treatment group. A mean describes the group average, while the standard deviation describes how spread out individual values are around that average. The reported standard deviations are 21.52 ml/min for sirolimus and 15.5 ml/min for cyclosporine. These summaries describe variability among measured participants; they are not uncertainty intervals for the group means.

What does the mean difference represent?

The recalculated contrast is cyclosporine minus sirolimus. Its estimate is -3.351 ml/min, reflecting the direction and size of the difference between the posted group means under that subtraction order. The sign depends on which group is subtracted from which; it does not by itself show clinical importance. The confidence interval places uncertainty around the estimated contrast rather than around either group's mean separately.

What does the confidence interval tell us?

In general, a confidence interval describes a range of values compatible with the data and the method used to calculate it. The primary 95% interval runs from -14.97 to 8.272 ml/min and includes zero. This means the data do not clearly distinguish a nonzero mean difference from no difference using this interval. The interval also indicates that the estimate is not precise enough to rule out a range of differences in either direction. Statistical compatibility is not the same as proof that every value in the interval is equally likely, nor does the interval incorporate uncertainty about study design or missing outcomes.

What do the p-values contribute?

A p-value describes how unusual the observed data, or data more extreme, would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The unadjusted recalculation gives p = 0.572. The registry's reported ANOVA gives p = 0.608. The record does not state enough detail about the ANOVA implementation to explain the numerical difference between those analyses. The sponsor's reported test and the recalculation should therefore be kept distinct.

General statistical context: ANOVA is a method for comparing group means under a model that includes assumptions about the outcome and error structure. For a comparison of two groups, an ANOVA test addresses whether the means differ under that model. The registry record identifies ANOVA as the sponsor's method, but does not report diagnostic checks, adjustments, covariates or other implementation details. It would be inappropriate to infer those details from the method label alone.

The recalculated analysis is described as unadjusted and is based on posted group summary statistics. It is not a substitute for a complete participant-level analysis, and it cannot reproduce adjustments or data-handling decisions that might have been used in the sponsor's analysis. The record lists a pooled standard deviation of 18.75 and a standardized difference of -0.179 for the primary comparison. Such standardized summaries express a mean contrast relative to variability; they do not add independent evidence or establish clinical importance.

Why does the analysis population matter?

The primary endpoint is defined for patients who completed 12 months of study drug, and the posted summaries show 20 participants per group. In general, an analysis restricted to completers can differ from an analysis of all randomized participants if completion or outcome availability is associated with treatment or outcome. The registry record does not report how missing measurements were handled, whether any imputation was used, or whether the sponsor analyzed all randomized participants, all treated participants, or only those with observed outcomes. These unknowns limit assessment of the estimates' susceptibility to missing-data bias.

The registry record also lists a secondary creatinine-clearance measure at 3 months. Its mean difference and interval are recalculated from the posted summary statistics in the same general way, while the sponsor reports an ANOVA p-value. These are secondary analyses, and the record does not describe a multiplicity adjustment. General statistical context: when many outcomes or time points are tested, the chance of at least one apparently unusual result can rise unless the analysis accounts for the number and structure of tests. Without a prespecified hierarchy or adjustment details, isolated secondary p-values should be interpreted cautiously.

Planning illustrations use the observed effect as a starting point and consider smaller fractions of it. They are not evidence about the trial's achieved power. The original sample-size rationale and the trial's own design assumptions are not reported in the registry record. The planning calculations use stated assumptions for significance level, allocation and approximation, but those are illustrations for future planning rather than a description of the original study design.

General statistical context: over-dispersion is relevant when the observed variability is greater than a model expects, particularly for count outcomes. The primary endpoint is continuous and summarized with means and standard deviations; the registry record does not report an over-dispersion analysis. This concept should not be confused with the ordinary spread represented by the reported standard deviations.

11. Confidence Intervals and Precision

The primary estimated difference is -3.351 ml/min, with a 95% confidence interval from -14.97 to 8.272 ml/min. Because the interval includes zero, the posted result is compatible with no mean difference. It is also compatible with differences on either side of zero, including values that may matter clinically. The registry record does not define a threshold for clinical importance, so statistical precision cannot determine whether the interval's values would be important to patients or clinicians.

The interval is wide relative to the point estimate. This signals limited precision: the data do not pin down the between-group mean difference closely. The standard deviations, 21.52 ml/min in the sirolimus group and 15.5 ml/min in the cyclosporine group, describe substantial variation among individual observations, while the group summaries are based on 20 participants per arm. Variation and sample size both contribute to uncertainty, but the interval itself is the direct summary of uncertainty for the estimated contrast.

A confidence interval is not a range that contains the true effect with certainty, nor does inclusion of zero prove that the groups are identical. It is a method-based range whose interpretation depends on the analysis assumptions. The registry record does not report a clinically meaningful margin or an equivalence design. Consequently, the interval cannot be used to claim equivalence or noninferiority.

Interpretation is also limited by the endpoint population: patients who completed 12 months of study drug. The record does not explain outcome availability for other participants, reasons for non-completion, or missing-data methods. The displayed interval reflects the reported summary-statistic comparison, not uncertainty from potentially informative missingness or unreported analysis choices.

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, not total events. They are illustrative calculations based on the observed effect, rather than the original trial's sample-size plan. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the estimated participants per arm for a future study to have an 80% chance of detecting the chosen effect under the listed assumptions, if that effect and the assumptions hold. The 90% power column uses a higher target chance of detecting that effect, and therefore requires more participants per arm in the listed illustrations. These are planning quantities, not a guarantee that a future study will produce a particular result.

The rows vary the assumed effect: planning for 100% of the observed effect uses the observed estimate, while planning for 75% or 50% uses smaller effects. Smaller effects are harder to distinguish from random variation and need more participants. The posted calculations show that pattern across both power targets.

This is not observed power. It does not describe the probability that the completed trial detected its true effect, and it should not be used to reinterpret the trial's p-value. The observed estimate itself is uncertain, and planning from it can produce unstable requirements, especially when the estimated effect is small or imprecise. The calculations are best read as conditional illustrations of how assumed effect size and target power relate to participant requirements, not as evidence that the trial was adequately or inadequately designed.

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 = -3.351; pooled standard deviation σ = 18.753.
2. n = 2 × (1.96 + 0.842)² × 18.753² / -3.351² = 491.6, rounded up to 492 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 <- -3.351                      # observed difference in means
sigma <- 18.753046325864                     # 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(195273)
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 = 492 (80% power), 659 (90% power)
 75% of observed effect: n per arm = 874 (80% power), 1,171 (90% power)
 50% of observed effect: n per arm = 1,967 (80% power), 2,633 (90% power)
power.t.test: 492.6 
Simulated power at n = 492 per arm: 0.800 (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. Analyses Reported by the Sponsor

The registry's reported primary analysis is an ANOVA comparison, with p = 0.608. The unadjusted recalculation from the posted means, standard deviations and group sizes gives a mean difference of -3.351 ml/min, a 95% confidence interval from -14.97 to 8.272 ml/min, and p = 0.572. The record does not report enough methodological detail to explain the difference between the sponsor's test and the recalculation.

The recalculation is a simple summary-statistic analysis, not a reconstruction of the sponsor's full analysis. It may not reflect data-level choices, adjustments or modeling details that are not described in the registry record. The sponsor's ANOVA result should be understood as the reported analysis; the recalculation offers a transparent, unadjusted comparison of the posted summaries. The record does not identify a discrepancy flag, but that does not resolve the missing methodological detail.

Both p-values are consistent with the broad conclusion that the reported comparison does not provide clear statistical evidence of a difference. Neither establishes that the regimens are equivalent. The confidence interval from the recalculation is useful for seeing the range of mean differences compatible with that analysis, while the sponsor's p-value alone does not express the magnitude or precision of the contrast.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies several outcomes, including the primary 12-month creatinine-clearance measure and secondary outcomes related to acute rejection, survival and 3-month creatinine clearance. It reports one primary analysis and one secondary analysis in the posted numerical results. The record does not report a testing hierarchy, an adjustment for multiple comparisons, or a detailed statistical analysis plan. Without those details, the interpretation of secondary tests is less secure because repeated testing can increase the chance of at least one apparently positive finding.

The primary endpoint population is patients who completed 12 months of study drug. The posted summary counts are 20 participants per arm, while enrollment is listed as 61. The registry record does not explain participant flow, report reasons for non-completion, or state how many endpoint observations were missing. It also does not describe imputation, sensitivity analyses, or other missing-data procedures. No assumption about those procedures can be made from the posted summary alone.

In general, missing outcomes can bias a comparison if the likelihood of having a measured outcome is related to treatment assignment or the outcome itself. A completer-only summary can be informative about those who completed treatment, but may not represent the randomized groups if completion is selective. The registry record does not provide enough information to judge whether that concern applies in this study.

The record also does not make clear whether the sponsor's analysis followed an intention-to-treat principle or another analysis population. The reported endpoint definition and summary counts establish what is summarized, but not how all randomized participants were handled. These reporting gaps limit assessment of robustness and should be kept separate from the uncertainty represented by the confidence interval.

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

The posted primary results show similar average creatinine-clearance values in the two groups among patients who completed 12 months of study drug. The recalculated mean difference is small relative to the uncertainty around it, and the confidence interval includes zero. This is a description of the reported data, not a conclusion that the treatments are interchangeable or that any observed difference is unimportant.

The result does not establish equivalence or noninferiority. Those conclusions require an appropriate design and a prespecified margin defining how large a difference could be considered acceptable. Such a margin is not reported in the registry record. A non-significant test does not prove no effect; it indicates that the analysis did not clearly distinguish the observed data from the null comparison under its assumptions.

The endpoint is a calculated measure of kidney function, and the study used the Nankivell formula. The results do not by themselves establish effects on all aspects of kidney function, transplant outcomes, patient experience or long-term health. The registry record names rejection and survival among secondary outcomes, but numerical results for those outcomes are not reported in the registry record.

The comparison concerns two complete regimens. Because the regimens differ in more than one component, the contrast cannot isolate the effect of sirolimus, cyclosporine or any other individual drug. The trial's randomized design is relevant to comparing assigned regimens, but open-label conduct, the completer-defined primary population and unreported missing-data methods constrain interpretation.

These findings should therefore be read as an uncertain estimate of the mean difference in 12-month creatinine clearance for the reported endpoint population. They neither demonstrate a clear difference nor show that no clinically important difference exists. The registry record does not provide enough information to make broader claims about safety, survival or the overall balance of benefits and harms.

17. Why This Trial Matters Statistically

This trial illustrates why a point estimate and its uncertainty should be interpreted together. The posted group means are close, but the confidence interval spans a range of differences in both directions. Looking only at the point estimate could overstate certainty; looking only at a p-value could conceal the range of effects still compatible with the data.

It also highlights the distinction between not detecting a difference and demonstrating equivalence. The registry record reports a superiority-or-other analysis, but does not give an equivalence margin or noninferiority framework. A result that does not clearly reject a null comparison cannot answer whether any difference is small enough to be unimportant.

The study's primary endpoint population is defined by completion of 12 months of study drug. That makes the relationship between enrollment, randomization and the analyzed endpoint group important for interpretation. The registry record lists enrollment and outcome counts but does not provide participant flow or missing-data methods. Such omissions are not merely administrative: they limit the ability to judge whether the analyzed groups preserve the protection offered by randomization.

Finally, the record contrasts a sponsor-reported ANOVA with a simple unadjusted recalculation from summary statistics. This shows why an analysis method and its assumptions matter. Recalculations can aid transparency, but they cannot substitute for undocumented participant-level methods. The result is most informative when its estimate, uncertainty, population and reporting limitations are considered together.

18. 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 summaries apply to patients who completed 12 months of study drug, and the record does not give a participant flow accounting for the relationship between enrollment and those summaries. Reasons for missing endpoint measurements or non-completion are not reported in the registry record. That makes it difficult to assess whether the completer population remained comparable between groups.

The study was open-label, with masking listed as none. The registry record does not state whether outcome assessment or statistical analysis was masked. Creatinine clearance was calculated using the Nankivell formula, but no further measurement or validation details are reported. The endpoint is a surrogate measure of kidney function and should not be treated as a complete measure of transplant or patient outcomes.

The primary confidence interval is broad and includes zero. The record does not provide a clinically important difference threshold, so the clinical relevance of values within the interval cannot be determined from the reported comparison alone. It also does not report an equivalence or noninferiority margin, preventing those interpretations.

Although the record names rejection, patient and graft survival, and 3-month creatinine clearance as secondary outcomes, numerical results are not reported for all of them. Multiplicity handling and the planned hierarchy of outcomes are not reported. The detailed statistical plan, original sample-size justification, treatment doses and participant eligibility criteria are also not reported in the registry record.

The sponsor's ANOVA is identified, but its implementation details are limited. The summary-statistic recalculation is unadjusted and cannot account for unreported covariates, participant-level data decisions or missing-data methods. Finally, the comparison evaluates two multi-component regimens, so it cannot isolate the effect of a single drug.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Study Evaluating Sirolimus in Kidney Transplant Recipients — NCT00195273.
• Registry record last updated 2010-04-28; status last verified 2010-04.
• Results first posted 2009-09-07.
• 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.

22. Record Summary

The registry record describes a completed, randomized, open-label, parallel-group Phase 3 study of kidney transplant recipients receiving kidneys from older donors. The comparison was between sirolimus with daclizumab, mycophenolate and corticosteroids, and cyclosporine with mycophenolate and corticosteroids. Enrollment is listed as 61.

The primary endpoint was mean creatinine clearance at 12 months among patients who completed 12 months of study drug. The posted means were 56.8 ml/min for sirolimus and 53.45 ml/min for cyclosporine. The unadjusted recalculated difference was -3.351 ml/min, with a 95% confidence interval from -14.97 to 8.272 ml/min. The interval includes zero and remains broad.

The sponsor reported an ANOVA analysis. The registry record also lists secondary outcomes, but numerical results are posted for the 3-month creatinine-clearance measure only. Participant flow, missing-data methods, multiplicity handling and the original sample-size justification are not reported in the registry record.