RESCUE Study - Everolimus in Liver Transplantation Recipients With Renal Insufficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for RESCUE Study - Everolimus in Liver Transplantation Recipients With Renal Insufficiency (NCT00267189), a randomized phase 3 study. The primary outcome is Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl).

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, parallel-group, open-label study listed as completed in the registry. The official title describes a 6-month, multicenter comparison of an everolimus-based regimen with a calcineurin inhibitor-based regimen in maintenance liver transplant recipients. The registry reports enrollment of 145 participants. The primary endpoint timeframe was change from baseline to 6 months.

The two assigned regimens differed principally in the calcineurin inhibitor strategy. One group received reduced-dose calcineurin inhibitor plus everolimus, with or without steroids; the other continued a standard calcineurin inhibitor dose, with or without mycophenolic acid or azathioprine and with or without steroids. Everolimus is listed at 1.5 mg twice daily in the experimental arm description. The registry also lists steroids and the other immunosuppressive medicines as interventions.

The primary-outcome results report 71 participants in each group. Those outcome counts do not equal the total enrollment reported in the registry, and the record does not explain the difference. For the primary analysis, the record describes an intention-to-treat population as randomized participants who received at least one dose of study medication. It also says that participants with baseline and 6-month creatinine-clearance measurements were included in the analysis. The handling of missing 6-month measurements is only partly visible in the outcome description and is addressed separately.

The study was open-label, meaning treatment assignment was not masked. The registry does not report the method used to generate the random sequence, allocation concealment procedures, the detailed protocol, or the study's original sample-size justification. Although two secondary outcomes are named—efficacy failure and discontinuation of study medication—secondary outcome results are not reported in the registry record. The registry also lists no analyses for those outcomes.

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: Intention to treat (ITT) population includes all patients who were randomized to one of the treatment groups and received at least one dose of study medication. Patients with baseline and 6 month creatinine clearance were included in analysis. Missing values at 6 months were imputed using the last observation carried forward (LOCF) approach.

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 Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl), measured over From baseline to 6 months.

The primary endpoint was mean change from baseline in Cockcroft-Gault calculated creatinine clearance, in mL/min, from baseline to 6 months. Creatinine clearance is used as a calculated indicator of renal function. The study description frames the clinical question around renal function in maintenance liver transplant recipients with calcineurin inhibitor-related renal impairment, making this measure relevant to the question being studied.

The registry describes the Cockcroft-Gault calculation as using age at the sample date, body weight at the visit, serum creatinine concentration, and a sex-specific factor. Because body weight and creatinine can vary over time, the calculated value is a measure based on those inputs rather than a direct measurement of kidney function. The record states that the primary variable was assessed at all visits, while the reported primary comparison concerns change from baseline to 6 months.

A mean change summarizes the average direction and size of change across the analyzed participants. It does not describe the full distribution of individual responses, and it can conceal variation between participants. The reported standard deviations help convey that variation. In this study, the mean changes were 0.99 mL/min in the everolimus group and 2.26 mL/min in the control group, with standard deviations of 10.25 and 7.79 mL/min, respectively. The comparison is therefore about group averages, not a claim that every participant changed by the group mean.

7. Results Posted in the Registry

• Group 1 (Everolimus): mean 0.99 versus 2.26 on control; difference -1.27 (95% CI -4.26 to 1.72), standardized effect d = -0.14; z-test p = 0.406.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a numerical change in calculated creatinine clearance measured in mL/min. The reported summary for each group is a mean with a standard deviation. A mean describes the central average, while a standard deviation describes how dispersed individual observations are around that mean. The standard deviation is not the uncertainty of the estimated mean; uncertainty in the comparison is reflected by the standard error and the reported interval.

What does the mean difference represent?

The comparison is expressed as the everolimus-group mean minus the control-group mean. The recalculated unadjusted mean difference is -1.27 mL/min. A negative value means the observed average change was lower in the everolimus group than in the control group under that subtraction order. It does not by itself show whether a difference is statistically persuasive or clinically important. Those questions require consideration of the interval, the variability, the endpoint's context, and the study design.

What does the p-value tell the reader?

The unadjusted p-value is 0.406. In general, a p-value describes how compatible the observed data are with a statistical model in which the compared group means are equal, given the test's assumptions. A larger p-value is not evidence that the groups are exactly equal, and it is not the probability that the null hypothesis is true. The registry record does not report a detailed statistical analysis plan, including whether this test was prespecified or whether other covariates were included. The posted comparison is therefore best described as an unadjusted comparison based on the summary statistics.

Why does variability matter?

The outcome standard deviations are 10.25 mL/min in the everolimus group and 7.79 mL/min in the control group, while the pooled standard deviation is 9.103 mL/min. General statistical principle: greater participant-to-participant variability makes a group contrast less precise when sample size is held fixed. The posted interval is relatively broad compared with the point estimate and crosses zero, so the data do not pin down the direction and size of the average difference tightly.

Over-dispersion is a general concern when data vary more than a simple model expects. For a continuous endpoint summarized with means and standard deviations, large spread can reduce precision and may make distributional assumptions more consequential. The registry does not report checks of distributional assumptions, transformations, robust methods, or sensitivity analyses, so it is not possible to determine from this record whether such issues were assessed.

How should the interval be understood?

The reported interval runs from -4.265 to 1.725 mL/min. In general, a confidence interval gives a range of estimates compatible with the data and the method used, while reflecting sampling uncertainty. A narrow interval indicates greater precision than a wide one, all else equal. The interval's confidence level is not reported in the registry record, so no particular coverage level should be assumed from the available description. Since zero lies within the interval, the results do not exclude no average difference under the reported comparison.

The statistical comparison is based on summary quantities including group means, standard deviations, and group sizes. It is not an adjusted model estimate. The posted calculation uses 71 participants per group; the registry reports overall enrollment of 145. The record does not explain why the primary outcome counts are lower than the enrollment total or whether exclusions and missing measurements account for the difference.

What does randomization contribute?

Random assignment is intended, in general, to make treatment groups comparable on average with respect to both measured and unmeasured baseline characteristics. It does not guarantee identical groups, especially in a finite study, and it does not remove uncertainty in an estimated treatment contrast. The registry identifies the study as randomized but does not report the sequence-generation or allocation-concealment methods. The open-label design means treatment assignment was not masked, a feature that can be relevant to outcomes affected by participant or clinician decisions. The primary endpoint is calculated from clinical measurements, but the record does not describe measurement oversight or masking of assessors.

The analysis population is described as randomized participants who received at least one dose of study medication, with baseline and 6-month creatinine-clearance values included. This description combines an intention-to-treat label with a treatment-exposure requirement and an endpoint availability requirement. The complete handling of missing values cannot be established: the registry text says 6-month missing values were imputed using the last o, but the description is truncated. The specific imputation procedure and its assumptions are not reported in the registry record.

Finally, the numerical planning illustrations are based on the observed effect and stated assumptions; they are not evidence about the study's original design or the probability that the trial detected an effect. The registry does not report the original sample-size justification, prespecified analysis details, interim analyses, or a multiplicity plan. These omissions limit what can be concluded about how the reported statistical test fits into the trial's full analysis strategy.

10. Confidence Intervals and Precision

The unadjusted mean difference is -1.27 mL/min, and its reported interval extends from -4.265 to 1.725 mL/min. This interval conveys uncertainty around the estimated contrast: the point estimate is a single summary, while the interval shows a range of values compatible with the data and the method used. Its confidence level is not reported in the registry record.

The interval includes zero, so the posted results are compatible with no average difference as well as with differences in either direction. The interval also includes values on both sides of the point estimate, demonstrating that the estimate is not precise enough to settle the direction of the contrast. It should not be read as showing that every value within its endpoints is equally plausible, or as a range containing individual participants' changes.

The group standard deviations—10.25 mL/min for the everolimus group and 7.79 mL/min for the control group—describe variability among observations rather than uncertainty in the mean difference. The pooled standard deviation is 9.103 mL/min. Taken together with the interval, these summaries indicate that the estimated average contrast is uncertain relative to the variation in the outcome.

Precision is also affected by what information is available about analysis and missing data. The primary-outcome groups each include 71 participants, while overall enrollment is reported as 145. The registry does not explain this difference. The analysis description mentions imputation for missing 6-month values but is cut off before specifying the complete approach. The interval should therefore be interpreted alongside these reporting limitations rather than as a complete account of uncertainty from every possible source.

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 events. They are illustrations based on the observed effect, rather than the trial's own original design calculation. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers an effect to detect expressed as a fraction of the observed effect: 100%, 75%, or 50%.

The 80% power column gives the number of participants per arm in the planning calculation for an 80% chance of detecting the specified effect under those assumptions, if that effect is the true one. The 90% power column gives the corresponding participants per arm for a 90% chance. These are design calculations, not a description of the probability that the completed study found a real effect. This is not observed power.

The required participants per arm are 807 for 80% power and 1,080 for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, the corresponding figures are 1,434 and 1,920. For 50% of the observed effect, they are 3,227 and 4,320. Smaller effects require more participants to distinguish them from random variation under otherwise unchanged assumptions. The figures are not a recommendation or a reconstruction of the original trial design. The registry does not report the trial's original sample-size justification, and the planning calculations use a normal approximation rather than a documented protocol analysis plan.

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 = -1.270; pooled standard deviation σ = 9.103.
2. n = 2 × (1.96 + 0.842)² × 9.103² / -1.270² = 806.6, rounded up to 807 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 <- -1.27                      # observed difference in means
sigma <- 9.10347735758155                     # 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(267189)
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 = 807 (80% power), 1,080 (90% power)
 75% of observed effect: n per arm = 1,434 (80% power), 1,920 (90% power)
 50% of observed effect: n per arm = 3,227 (80% power), 4,320 (90% power)
power.t.test: 807.5 
Simulated power at n = 807 per arm: 0.803 (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 names two secondary outcomes: the percentage of patients with efficacy failure, defined as biopsy-proven acute rejection, graft loss, or death, and the number of patients with discontinuation of study medication. Results for these outcomes are not reported in the registry record. The record lists three outcome measures in total, but only the primary outcome has numerical results in the material available. It reports no analyses for secondary outcomes.

Multiplicity refers, in general, to the increased chance of at least one misleading positive result when several outcomes, time points, or comparisons are tested. A prespecified strategy may address that issue through test ordering, adjusted significance thresholds, or another approach. The multiplicity strategy for this study is not reported in the registry record. The record also does not report whether there were additional prespecified or exploratory outcomes beyond those named.

The primary outcome population is described as randomized participants who received at least one dose of study medication. The description further says that participants with baseline and 6-month creatinine clearance were included. That is an important qualification: the analysis population as described is not simply all randomized participants regardless of treatment exposure or outcome availability. The registry reports 71 analyzed participants in each group, while enrollment was 145; the reason for the difference is not stated.

The primary outcome description says missing 6-month measurements were imputed using the last o, but the text ends before the full phrase or method is given. The exact imputation rule, the number of missing values, and the assumptions supporting the procedure are not reported in the registry record. No sensitivity analysis for missing data is reported. Without these details, it is not possible to assess whether the primary result is robust to alternative missing-data assumptions.

The record also does not report interim analyses, a complete statistical analysis plan, or the study's approach to model selection and covariate adjustment. Those details should not be inferred from the endpoint summaries or planning illustrations.

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: hyperpyrexia (2.8%), dyspnoea (2.8%), anaemia (2.7%), pyrexia (2.7%), leukopenia (1.4%).

The serious adverse-event summaries report 18 affected participants among 72 at risk in the everolimus group and 14 among 73 at risk in the control group. These are counts of participants reported as affected, with the corresponding at-risk group sizes stated by the registry. They should not be interpreted as event rates without further details about how the registry defined and collected these summaries.

The registry lists the most frequent serious-event terms with percentages: hyperpyrexia, 2.8%; dyspnoea, 2.8%; anaemia, 2.7%; pyrexia, 2.7%; leukopenia, 1.4%; and thrombotic microangiopathy, 1.4%. The record does not give the denominator or explain in this listing whether the percentages refer to participants or events. It also does not provide a group-specific breakdown for those terms in the information available.

Other adverse events were reported for 58 of 72 participants in the everolimus group and 31 of 73 in the control group. Death counts are not reported in the registry record. These summaries are descriptive. They do not, by themselves, establish that a regimen caused an event or provide a complete comparison of safety, timing, severity, or duration.

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

The primary result estimates the difference between group averages in change in Cockcroft-Gault calculated creatinine clearance from baseline to 6 months. The everolimus group mean change was 0.99 mL/min, and the control group mean change was 2.26 mL/min. The unadjusted difference was -1.27 mL/min, with a reported interval from -4.265 to 1.725 mL/min and an unadjusted p-value of 0.406. The interval includes zero and spans both negative and positive values, so the direction and size of the underlying average contrast remain uncertain.

These data do not establish that the regimens are equivalent. A result that does not distinguish a difference from zero is not the same as evidence that any difference is negligible. The registry does not report a prespecified equivalence or non-inferiority margin, and the posted interval is not presented as an equivalence analysis. Nor do the summaries establish that one regimen is superior or inferior.

The primary measure is a calculated renal-function indicator and the comparison covers 6 months. The results therefore do not, on their own, describe longer-term renal outcomes, other aspects of transplant efficacy, or all consequences of changing immunosuppressive treatment. Although the registry's study purpose includes maintaining efficacy, the named secondary efficacy-failure outcome has no numerical results reported in the registry record.

The adverse-event summaries provide counts of affected participants and a list of serious-event terms, but they do not supply enough detail to determine causal relationships or characterize the full balance of harms and benefits. The registry does not report death counts. Safety and efficacy interpretation also depends on information not fully documented in the available record, including complete missing-data handling and the detailed analysis plan.

Accordingly, the result is best understood as an imprecise unadjusted comparison of mean changes in the analyzed groups. It should not be converted into advice about treatment choice or taken as a statement that a treatment works or does not work.

16. Why This Trial Matters Statistically

This trial raises a common biostatistical problem: how to interpret a small estimated group contrast when the outcome varies substantially between participants. The mean changes are 0.99 mL/min and 2.26 mL/min, while the group standard deviations are 10.25 mL/min and 7.79 mL/min. The resulting interval for the unadjusted difference, -4.265 to 1.725 mL/min, crosses zero. The point estimate alone would give an incomplete account; uncertainty and variability are central to interpretation.

The endpoint also illustrates how a clinical measure can depend on a calculation. Cockcroft-Gault creatinine clearance uses age, body weight, serum creatinine, and a sex-specific factor. Changes in the calculated result can reflect changes in the inputs as well as changes in renal function. Careful reporting of measurement timing, calculation procedures, missing values, and analysis choices is therefore important for assessing what the endpoint captures.

There is also a distinction between a study's observed result and planning calculations. The participant-per-arm illustrations show how a hypothetical future design would scale under stated assumptions and effect sizes. They are not evidence that the completed study had a particular probability of success, and they do not reveal the original sample-size rationale. Keeping that distinction clear prevents planning scenarios from being mistaken for results.

Finally, the registry's reporting gaps matter statistically. The analysis population is described with exposure and measurement requirements, while the handling of missing 6-month outcomes is truncated. Secondary outcomes are named but not numerically reported. These are not reasons to discard the primary estimate; they are reasons to qualify the conclusions and to recognize that a complete assessment requires transparent reporting of analysis populations, missing-data methods, and all planned outcomes.

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 registry record does not report the original sample-size justification, the detailed statistical analysis plan, interim analyses, or a multiplicity strategy. It identifies the study as randomized but does not describe sequence generation or allocation concealment. The open-label design is reported, but masking of endpoint assessors is not described.

The primary outcome analysis is reported for 71 participants per group, compared with total enrollment of 145. The reason for the difference is not reported in the registry record. The outcome population is described as randomized participants who received at least one study-medication dose and had baseline and 6-month creatinine-clearance values. This population definition may not include every randomized participant.

The missing-data statement is incomplete: it says that missing 6-month values were imputed using the last o, without identifying the full procedure. The number of missing values and sensitivity analyses are not reported. The confidence level for the interval around the mean difference is also not reported in the registry record.

Numerical results for the named secondary outcomes are absent, as are death counts in the safety summary. The serious-event term percentages are listed without a stated denominator or group-specific breakdown. These limitations restrict interpretation of the overall efficacy and safety picture. The posted primary comparison is unadjusted, and the record does not describe assumption checks or adjusted analyses.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: RESCUE Study - Everolimus in Liver Transplantation Recipients With Renal Insufficiency — NCT00267189.
• Registry record last updated 2011-04-13; status last verified 2011-04.
• Results first posted 2011-04-07.
• 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.

21. Record Summary

The RESCUE Study was a completed, phase 3, randomized, open-label, parallel-group study in maintenance liver transplant recipients with renal impairment. Its official title describes a 6-month, multicenter comparison of an everolimus-based regimen with a calcineurin inhibitor-based regimen. Registry enrollment was 145.

The primary outcome was mean change from baseline to 6 months in Cockcroft-Gault calculated creatinine clearance. The reported means were 0.99 mL/min for everolimus and 2.26 mL/min for control; the unadjusted mean difference was -1.27 mL/min, with an interval from -4.265 to 1.725 mL/min and p = 0.406.

The registry names efficacy failure and study-medication discontinuation as secondary outcomes but does not report their numerical results. The primary outcome analysis includes 71 participants per group, and the reason for the difference from total enrollment is not reported. The missing-data description is incomplete, limiting assessment of the analysis.