Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients (NCT00622869), a randomized phase 3 study. The primary outcome is Incidence Rate of Composite Efficacy Failure From Randomization to Month 12.

2. Clinical Question

The trial addressed whether two strategies involving everolimus and reduced tacrolimus exposure were associated with different rates of composite efficacy failure than control-dose tacrolimus among de novo liver transplant recipients. The primary outcome covered the period from randomization to Month 12 and combined treated biopsy-proven acute rejection, graft loss, or death.

The composite combines several clinically important events into one endpoint. Its components were treated biopsy-proven acute rejection, graft loss, and death. The registry record also describes renal function and fibrosis progression in hepatitis C virus-positive patients as issues the trial was designed to address. The primary result is the composite endpoint; it does not by itself provide the separate effects on those other issues.

3. Trial Design

This was a Phase 3, randomized, controlled, parallel-group study with no masking. The official title describes a 24 Month, Multicenter, Open-label study in de novo liver transplant recipients. The registry record lists the study as completed, with a start date of 2008-01 and primary completion in 2012-04. Enrollment was 719.

Three treatment strategies were represented. The Everolimus + Reduced Tacrolimus arm combined low-dose tacrolimus, everolimus, and corticosteroids. The Tacrolimus Elimination arm used low-dose tacrolimus until Month 4, then eliminated tacrolimus, alongside everolimus and corticosteroids. The Tacrolimus Control Arm used control-dose tacrolimus and corticosteroids. The posted arm sizes for the primary outcome were 245, 231, and 243, respectively.

The primary outcome was assessed from randomization to Month 12, although the official study title describes a 24-month study. The registry record lists secondary outcomes for composite efficacy failure through Month 24, treated biopsy-proven acute rejection at Months 12 and 24, and change in renal function at Months 12 and 24. Three secondary outcomes are posted. The registry record does not report the original sample-size justification, the detailed statistical analysis plan, or interim-analysis procedures.

Because the study was open-label, treatment assignment was not masked. Randomization supports comparisons between assigned groups, while the absence of masking is relevant context for interpreting outcomes and trial conduct. The registry record identifies the primary outcome population as all randomized patients, the intent-to-treat population.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat population: All randomized patients.

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 Incidence Rate of Composite Efficacy Failure From Randomization to Month 12, measured over Randomization to Month 12.

The primary endpoint was the incidence rate of composite efficacy failure from randomization to Month 12. A participant met the composite endpoint if treated biopsy-proven acute rejection, graft loss, or death occurred. Combining events creates a single outcome that captures several forms of failure relevant to the transplanted graft and the recipient, rather than relying on one event type alone. The registry record describes renal function, early tacrolimus reduction or discontinuation, and fibrosis progression in hepatitis C virus-positive patients as important issues motivating the trial.

The registry defines biopsy-proven acute rejection as acute rejection confirmed by biopsy with a Rejection Activity Index score of at least 3. Treated biopsy-proven acute rejection required that the biopsy-proven rejection be treated with anti-rejection therapy. The Rejection Activity Index scores portal inflammation, bile duct inflammation damage, and venous endothelial inflammation. Each category is scored from 0, absent, to 3, severe; the total ranges from 0 to 9, with higher scores indicating greater rejection.

Graft loss was presumed on the day a patient was newly listed for a liver graft, received a graft re-transplant, or died. The registry record says incidence rates were estimated with the Kaplan-Meier product-limit formula. The composite is useful for summarizing whether any defined event occurred over the specified follow-up, but the combined result does not show which component accounts for the observed pattern. Separate component results are not reported in the registry record.

7. Results Posted in the Registry

• Everolimus + Reduced Tacrolimus: 6.5% (16/245) versus 9.9% (24/243) on control; risk difference -3.3 percentage points (95% CI -8.2 to 1.5), risk ratio 0.66 (0.36–1.21); unadjusted two-proportion z-test p = 0.178.
• Tacrolimus Elimination: 24.2% (56/231) versus 9.9% (24/243) on control; risk difference 14.4 percentage points (95% CI 7.7 to 21.0), risk ratio 2.45 (1.58–3.82); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a time-to-event style outcome summarized as an incidence rate over follow-up. The registry record states that Kaplan-Meier product-limit estimation was used. This method estimates the probability of remaining free of the event over time while incorporating the timing of events and, where applicable, incomplete follow-up. In general, Kaplan-Meier estimates can use information from participants whose follow-up ends before the study endpoint, under assumptions about the reasons follow-up ends. The registry record does not describe censoring rules or how incomplete follow-up was handled.

What does the composite endpoint count?

The event is the first occurrence of any qualifying component: treated biopsy-proven acute rejection, graft loss, or death. Combining outcomes can provide a broader measure of efficacy failure when several events are relevant. The trade-off is that a composite result can be driven more by one component than another. The registry record does not provide the component-specific primary outcome results, so the overall arm percentages cannot identify which component contributed most.

The rejection definition includes biopsy confirmation and a Rejection Activity Index score of at least 3. Treatment with anti-rejection therapy was also required for the event to count as treated biopsy-proven acute rejection. This definition is narrower than counting all suspected rejection episodes: it requires the stated biopsy and treatment criteria. The score combines three pathology categories, each rated from 0 to 3, to produce a total score ranging from 0 to 9.

What does a risk difference express?

A risk difference compares the event risks in two groups by subtracting one group’s risk from the other’s, according to the comparison direction. A value of zero corresponds to equal risks. Values below or above zero indicate a difference in opposite directions, depending on which group is subtracted from which. The posted risk differences are -0.034 for Everolimus + Reduced Tacrolimus versus control and 0.144 for Tacrolimus Elimination versus control. These are unadjusted comparison estimates, not adjusted model results reported by the registry.

A confidence interval describes a range of estimates compatible with the data under the method used, subject to its assumptions. It is not a range containing a known fixed proportion of individual participant outcomes. For the reduced-tacrolimus comparison, the interval extends from -0.082 to 0.015 and includes zero. For the elimination comparison, the interval extends from 0.077 to 0.210 and does not include zero. The interval’s position and width are important alongside the point estimate.

How should the p-values be read?

The unadjusted p-value tests a null hypothesis of no difference for the comparison under the statistical method used. The posted p-values are 0.178 for Everolimus + Reduced Tacrolimus versus control and <0.001 for Tacrolimus Elimination versus control. A p-value is not the probability that the null hypothesis is true, nor does it measure the clinical importance of an effect. These values are labelled unadjusted. Whether and how the trial accounted for multiple comparisons is not reported in the registry record.

The arm-level primary endpoint percentages are 6.7%, 24.2%, and 9.7%. The pairwise comparison records also contain event counts and group sizes for unadjusted calculations. The registry identifies the primary analysis population as all randomized patients. It does not report whether the posted pairwise statistics reproduce the sponsor’s prespecified analysis or whether any covariate adjustment was planned.

What remains unknown about the analysis?

Randomization and the parallel-group design identify the broad comparison structure, but they do not supply every analytic detail. The registry record does not report the original sample-size justification, missing-data rules, interim analyses, multiplicity procedures, or a full statistical analysis plan. It also does not report details such as the censoring approach for the Kaplan-Meier estimates. These details matter because analysis choices can affect estimates, uncertainty, and interpretation. Their absence should be treated as missing documentation, not as evidence that a particular procedure was or was not used.

General statistical principle: estimates are more informative when considered together with their uncertainty and the design that produced them. A point estimate alone does not show how precisely the effect is known. Likewise, a statistically significant result does not establish clinical importance, and a non-significant result does not prove equivalence. The posted endpoint, interval estimates, and study characteristics therefore need to be read together.

10. Confidence Intervals and Precision

Precision is reflected by the uncertainty around an estimate, commonly described with a confidence interval. A narrow interval indicates that the data are compatible with a more limited range of values under the analysis assumptions; a wider interval indicates greater uncertainty. The intervals concern the unadjusted risk differences, not the arm percentages themselves.

For Everolimus + Reduced Tacrolimus versus control, the risk difference is -0.034 and the 95% confidence interval is -0.082 to 0.015. Because the interval includes zero, the data are compatible with a small difference in either direction as well as values farther from zero within the interval. The estimate should not be treated as proof that the groups had identical risks.

For Tacrolimus Elimination versus control, the risk difference is 0.144 and the 95% confidence interval is 0.077 to 0.210. This interval is entirely above zero under the comparison’s stated direction. It nevertheless spans a range of possible effect sizes, so the point estimate is not known with exactness.

The registry record does not provide confidence intervals for the arm-level Kaplan-Meier percentages. The confidence intervals for the pairwise risk differences therefore should not be presented as intervals around those percentages. Both comparisons are unadjusted, and the registry record does not report whether multiplicity was handled. Precision describes statistical uncertainty under the analysis; it does not resolve limitations in endpoint interpretation, missing-data documentation, or generalizability.

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 calculation. For these binary-outcome comparisons, the figures are participants per arm, not total events. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect set to the stated fraction of the observed effect. The trial’s own original design assumptions are not reported in the registry record.

The 80% power column gives the planned number of participants per arm for a hypothetical study to have an 80% chance of detecting the specified effect under those assumptions, if that effect and the calculation assumptions were correct. The 90% power column uses the same interpretation with a higher target chance of detection. Neither column describes the chance that the observed result is true, and this is not observed power.

For Everolimus + Reduced Tacrolimus versus control, planning for 100% of the observed effect gives 1,055 participants per arm for 80% power and 1,412 participants per arm for 90% power. Planning for 75% of the observed effect gives 1,963 and 2,628 participants per arm, respectively; planning for 50% gives 4,611 and 6,173.

For Tacrolimus Elimination versus control, planning for 100% of the observed effect gives 107 participants per arm for 80% power and 142 participants per arm for 90% power. Planning for 75% gives 174 and 233, respectively; planning for 50% gives 354 and 473. Smaller effects require more participants to detect under the same assumptions. These illustrations are comparisons of hypothetical planning scenarios, not evidence about the trial’s actual power or its design process.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.099; treatment proportion p₁ = 0.065; average p̄ = 0.082.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3881 = 0.7606.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3874 = 0.3260.
4. n = (0.7606 + 0.3260)² / (-0.0335)² = 1,054.7, rounded up to 1,055 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
p0 <- 0.0987654320987654                          # control proportion
p1 <- 0.0653061224489796                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(622869)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 1,055 (80% power), 1,412 (90% power)
 75% of observed effect: n per arm = 1,963 (80% power), 2,628 (90% power)
 50% of observed effect: n per arm = 4,611 (80% power), 6,173 (90% power)
power.prop.test: 1054.7 
Simulated power at n = 1,055 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 trial has three arms and two posted pairwise comparisons of the primary endpoint against the tacrolimus control arm. It also lists secondary outcomes for composite efficacy failure through Month 24, treated biopsy-proven acute rejection at Months 12 and 24, and change in renal function at Months 12 and 24. The registry record lists three posted secondary outcomes. Testing multiple outcomes or comparisons can increase the chance of at least one apparently notable result by chance if no multiplicity strategy is used.

The two posted primary pairwise p-values are described as unadjusted. Whether the trial used a prespecified testing hierarchy, family-wise error control, or another multiplicity approach is not reported in the registry record. The registry also does not report adjusted p-values or adjusted confidence intervals. Consequently, the individual p-values should not be assumed to account for the full set of comparisons or outcomes.

The primary population is described as intent-to-treat, meaning all randomized patients. The record does not report how missing outcome information was handled, how participants with incomplete follow-up contributed to the primary analysis, or whether any alternative analysis populations were used. For a Kaplan-Meier outcome, the handling of incomplete follow-up and censoring can be important, but those details are not reported in the registry record.

The record lists four outcome measures and zero analyses. This limits the amount of detail available about analytic specifications and results beyond the posted primary comparison. Interim-analysis procedures, the original sample-size justification, and a detailed statistical analysis plan are not reported in the registry record. These are documentation gaps; they do not establish that a given method was omitted from the trial conduct. They do mean that the posted results cannot be fully evaluated against a prespecified analysis framework using the registry record alone.

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: liver transplant rejection (10.5%), pyrexia (8.7%), abdominal hernia (4.8%), diarrhoea (4.8%), cholangitis (4.8%).

The serious adverse event figures report, for each arm, the number at risk and the number affected. For Everolimus + Reduced Tacrolimus, 245 were at risk and 138 were affected. For Tacrolimus Elimination, 229 were at risk and 152 were affected. For Tacrolimus Control Arm, 242 were at risk and 131 were affected. These are counts; no percentages should be inferred from them.

The registry record lists serious adverse event terms and percentages, including Liver transplant rejection at 10.5%, Pyrexia at 8.7%, Abdominal hernia at 4.8%, Diarrhoea at 4.8%, Cholangitis at 4.8%, and Renal failure acute at 4.5%. The record does not establish in these figures which arm each term corresponds to, so they should not be assigned to a particular treatment group. Death counts are not reported in the registry record.

Adverse-event summaries describe events recorded during the study; they do not by themselves establish that an intervention caused an event. The registry record’s serious-event counts also do not supply event timing, duration, severity distribution, or a comparative safety analysis. Interpret these figures as descriptive reporting, alongside the trial’s design and the limits of the posted safety detail.

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

The primary endpoint results show different observed patterns across the three randomized arms for composite efficacy failure from randomization to Month 12. The arm-level percentages were 6.7% for Everolimus + Reduced Tacrolimus, 24.2% for Tacrolimus Elimination, and 9.7% for Tacrolimus Control Arm. The unadjusted pairwise estimate for the reduced-tacrolimus strategy has a confidence interval that includes zero, whereas the interval for the elimination strategy versus control lies above zero under the comparison direction.

These results do not establish that a treatment works or does not work in general. They describe this trial’s posted outcome under its design, population, endpoint definitions, and follow-up. A confidence interval gives uncertainty around an estimated contrast, while the p-value addresses compatibility with a specified null hypothesis under the analysis. Neither alone gives the probability that a treatment is beneficial or harmful.

The endpoint combines treated biopsy-proven acute rejection, graft loss, and death. The overall composite does not show which component produced the observed differences. The registry record does not report separate primary component results, and it does not provide enough information to determine how missing data, censoring, or multiplicity were handled. The posted primary outcome population is intent-to-treat, defined as all randomized patients.

The official title describes a 24-month study, but the primary result is for Month 12. The record lists additional outcomes through Month 24 and at Months 12 and 24, but their detailed results are not reported in the registry record. The findings therefore should not be extended to those later outcomes or to specific subgroups, including hepatitis C virus-positive patients, without corresponding results.

General interpretation principle: statistical evidence, clinical relevance, and applicability are related but distinct. The trial’s numerical estimates and precision are relevant to the stated comparison; they do not answer every question about long-term outcomes, individual components, or other patient groups.

16. Why This Trial Matters Statistically

This trial is statistically informative because it compares distinct tacrolimus strategies in a randomized, parallel-group design and reports a defined composite endpoint. The comparison makes clear why arm-level percentages and pairwise estimates need to be read together: the outcome was not the same across the three arms, and the uncertainty differs between the two posted comparisons.

The reduced-tacrolimus comparison has a risk-difference interval that crosses zero, while the elimination comparison has an interval entirely above zero under the stated comparison direction. This illustrates a central statistical distinction: a point estimate describes the direction and size of an observed contrast, while its confidence interval indicates how much uncertainty remains. Neither measure replaces consideration of endpoint definitions, study conduct, or the analysis framework.

The composite endpoint is also a useful reminder that one summary can combine events with different meanings. A result for the combined outcome cannot identify whether rejection, graft loss, or death accounts for the pattern. Component-level reporting would be needed to answer that question. The record’s definition of rejection shows how an endpoint’s operational criteria shape what is counted.

Finally, the record makes visible important limits in registry-based interpretation. It identifies randomization, masking status, the primary population, and Kaplan-Meier estimation, but does not report several details needed to reconstruct the full statistical plan. A careful reading distinguishes what the posted estimates support from what remains undocumented, rather than treating a p-value or a single percentage as a complete account of the evidence.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The study was open-label, so treatment assignment was not masked. This is relevant context for interpreting a trial’s conduct, although the registry record does not describe how awareness of assignment affected outcome assessment or other trial procedures. The primary endpoint includes a biopsy-confirmed and treated rejection component, alongside graft loss and death, and a composite result does not reveal the contribution of each component.

The primary outcome is reported through Month 12 in a study whose official title describes 24 months. Although the registry lists later secondary outcomes, their results are not reported in the registry record. The record also does not provide separate primary endpoint results for hepatitis C virus-positive participants, despite mentioning fibrosis progression in that group as an issue motivating the study.

The posted primary outcome population is all randomized patients, but missing-data procedures, censoring details, and alternative analysis populations are not reported in the registry record. The original sample-size justification, interim-analysis procedures, multiplicity approach, and full statistical analysis plan are also not reported. These gaps limit assessment of how the posted analyses relate to the planned analyses.

The serious adverse event summaries include counts and listed terms, but the record does not give a full comparative safety analysis or enough information to connect each listed term to a treatment group. Death counts are not reported in the registry record. These limitations call for restraint in interpreting safety and efficacy beyond the results and definitions that are actually posted.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients — NCT00622869.
• Registry record last updated 2013-05-27; status last verified 2013-05.
• Results first posted 2013-05-20.
• 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

NCT00622869 is a completed, randomized, Phase 3, open-label, parallel-group study in de novo liver transplant recipients. The official title describes a 24-month multicenter study. Enrollment was 719; the registry record lists a start date of 2008-01 and primary completion in 2012-04.

The three strategies were everolimus with reduced tacrolimus, everolimus with tacrolimus eliminated after Month 4, and control-dose tacrolimus. The primary endpoint was composite efficacy failure from randomization to Month 12, defined as treated biopsy-proven acute rejection, graft loss, or death. The registry reports Kaplan-Meier estimation and identifies the primary population as all randomized patients.

Posted arm percentages were 6.7%, 24.2%, and 9.7%, respectively. The unadjusted risk-difference comparison was -0.034 for Everolimus + Reduced Tacrolimus versus control and 0.144 for Tacrolimus Elimination versus control. The registry record does not report the original statistical plan, missing-data procedures, or multiplicity approach.