Comparison of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release in Human Leukocyte Antigen (HLA) Sensitized Kidney Transplant Recipients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparison of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release in Human Leukocyte Antigen (HLA) Sensitized Kidney Transplant Recipients (NCT04225988), a randomized phase 4 study. The primary outcome is Number of Participants With Biopsy-proven Acute Rejection.

2. Clinical Question

3. Trial Design

NCT04225988 is a completed Phase 4 randomized, open-label, controlled pilot trial with a parallel-group design. Its official title describes a prospective comparison of extended-release tacrolimus, Envarsus XR, with immediate-release tacrolimus for suppression of donor-specific antibodies in HLA-sensitized kidney transplant recipients. The registry record lists enrollment as 20 and gives a start date of 2020-01-09 and a primary completion date of 2023-07-11.

Recipients assigned to extended-release tacrolimus and recipients assigned to immediate-release tacrolimus also received standard-dose mycophenolate and prednisone for maintenance immunosuppression, according to the arm descriptions. Because masking is listed as none, the trial was open-label: treatment assignment was not masked according to the registry record. The record does not report how randomization was generated, whether allocation was concealed, or how treatment adherence was assessed.

The primary outcome was the number of participants with biopsy-proven acute rejection within 12 months of transplant. The registry summary also identifies donor-specific HLA antibodies, estimated glomerular filtration rate, and donor-derived cell-free DNA among the outcomes assessed. Four secondary outcomes are posted: participants with de novo donor-specific antibodies, persistent pre-existing donor-specific antibodies, eGFR, and donor-derived cell-free DNA. The registry record does not report a detailed protocol, the rationale for the enrollment target, or the timing and analysis plans for each secondary outcome.

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: Of the total 28 participants ages 18 and older screened, 20 were enrolled in this single-center, open-label, randomized controlled trial design pilot study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who completed their 12 month visit were assessed.

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 Number of Participants With Biopsy-proven Acute Rejection, measured over 12 months.

The primary endpoint counts participants with biopsy-proven acute rejection within 12 months of transplant. It is a binary outcome at the participant level: a participant either had a qualifying event during the stated period or did not. The posted outcome is expressed as counts, rather than as a continuous measurement such as eGFR.

Biopsy-proven rejection is a clinically defined event, and counting affected participants gives a direct description of how often that event occurred in each assessed group. In general, a binary endpoint can be useful when the clinical question concerns whether an event occurred during a defined follow-up period. The count alone, however, does not show the precision of the estimated event frequency or quantify the comparative effect between treatments.

The registry record says the endpoint was assessed among participants who completed their 12-month visit. It reports 1 participant in the extended-release group and 2 in the immediate-release group with biopsy-proven acute rejection; the corresponding group sizes reported for this outcome are 8 and 10. The registry record does not report an inferential comparison or confidence interval. The outcome description uses the word comparable, but no statistical margin or decision rule for establishing comparability is reported.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a count endpoint tell the reader?

The primary endpoint records how many assessed participants experienced biopsy-proven acute rejection during the stated follow-up period. For a binary outcome, the event count is an intuitive starting point: it records the number of participants meeting the event definition. The group size supplies context for that count. Counts alone, however, are not a full comparison. A statistical comparison typically estimates how the event frequency differs between groups and how uncertain that estimate is.

In general, an effect estimate describes the magnitude and direction of a contrast, while a confidence interval describes a range of values reasonably compatible with the data under the method's assumptions. A narrow interval indicates greater precision than a wide interval. When event counts are limited, estimates can be imprecise, and small changes in observed counts can have substantial influence. No effect estimate or confidence interval for the primary comparison is reported in the registry record.

Why is a significance test not enough?

In general, a hypothesis test evaluates how compatible the observed data are with a specified null hypothesis under a statistical model. A p-value, if reported, would not itself measure the probability that a treatment works, nor would it establish that groups are equivalent. Statistical significance and clinical importance are different questions: the first concerns evidence relative to a model and threshold, while the second requires interpretation of the effect size in context.

The registry record lists no posted analyses for this endpoint and says values are missing or not estimable for a two-arm comparison of the binary outcome. There is consequently no p-value to interpret and no documented analysis method to describe as the trial's inferential approach. A comparison of the event counts should not be treated as a substitute for an analysis that accounts for uncertainty.

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable in expectation with respect to measured and unmeasured factors at the time of assignment. It does not guarantee identical groups in a particular trial, especially when enrollment is limited. Randomization also does not resolve questions about missing outcomes, treatment adherence, or analysis populations. The registry record identifies the allocation as randomized but does not report the sequence-generation method, allocation concealment, or procedures for handling deviations from assigned treatment.

Masking is listed as none, consistent with an open-label design. In general, awareness of treatment assignment can influence care, reporting, or assessment, depending on the outcome and procedures. The primary endpoint is described as biopsy-proven, but the registry record does not report whether biopsy interpretation was blinded or how the event definition was applied. It would be inappropriate to assume safeguards that are not described in the registry record.

What are the planning illustrations?

Sample-size planning illustrations use the observed effect as a reference point and consider detecting a stated fraction of that effect under assumptions. The stated assumptions for these illustrations are a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. Such calculations are planning illustrations, not evidence that the trial had a particular probability of detecting an effect, and they are not observed power. The registry record does not report that these assumptions formed the trial's original design or that they were used in its protocol.

In general, planning calculations depend on the effect size one aims to detect, the chosen significance threshold, the desired power, the allocation scheme, and the statistical model. A calculation based on an observed effect can be particularly unstable when the estimate itself is imprecise. It should not be interpreted as a retrospective measure of whether the trial was adequately powered. No sample-size justification or original power calculation is reported in the registry record.

The stated normal approximation is an assumption of the planning illustration, not a reported method for analyzing the primary endpoint. In general, approximations can be less reliable when data are sparse or event counts are limited. For binary outcomes, methods that account for the discrete nature of the data may be considered, but the registry record does not specify an inferential method for this comparison. No alternative analysis should be attributed to the investigators without documentation.

What can be inferred from the posted analysis status?

The registry record's analysis count is zero, and it identifies the two-arm binary comparison as missing or not estimable. This means the available record supports a descriptive reading of the endpoint counts, not an inferential conclusion. A recalculation from summary counts, if undertaken, would be an unadjusted analysis and would not replace an analysis by the sponsor. The record does not indicate a discrepancy, but it also does not post a sponsor analysis for this endpoint.

In general, a result is best read by separating the observed data, the effect estimate, and its precision. Here, the observed data are counts in the assessed groups. The registry record does not report the comparative estimate or its uncertainty. That distinction is especially important when the clinical question uses language such as comparable: a conclusion of comparability ordinarily requires a prespecified margin and an analysis designed to assess it. Neither a margin nor such an analysis is reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Extended-release Tacrolimus", "Immediate-release Tacrolimus")
n      <- c(8, 10)
events <- c(1, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Extended-release Tacrolimus  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2
ARM  Immediate-release Tacrolimus  10  2  20.0  2.5  55.6  5.7  51.0  6.0  51.8

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists the primary endpoint of biopsy-proven acute rejection and four secondary outcomes: de novo donor-specific antibodies, persistent pre-existing donor-specific antibodies, eGFR, and donor-derived cell-free DNA. When a study assesses multiple outcomes, the chance of at least one apparently notable result can increase if each is tested separately without adjustment. In general, multiplicity procedures can control this issue, but the appropriate approach depends on the study's aims and prespecified testing strategy.

The registry record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a statistical analysis plan. It also does not report analyses for the secondary outcomes in the registry record for this result. The outcomes should therefore be read as distinct endpoints rather than as a single combined measure, and no claim about a controlled overall error rate can be made.

For the primary outcome, the registry record says that all participants who completed their 12-month visit were assessed. It reports group sizes of 8 and 10 for the endpoint, while enrollment is listed as 20. The reasons for the difference between enrollment and endpoint assessment are not reported in the registry record. There is no reported account of missingness by reason, imputation, sensitivity analysis, or a comparison of analysis populations.

In general, missing outcome data can affect interpretation if the likelihood of missingness is related to treatment assignment or outcome status. Restricting assessment to visit completers may yield a different result from an analysis that includes all randomized participants, depending on what happened to those without an assessed endpoint. The registry record does not report whether an intention-to-treat analysis or another prespecified population was used. The posted counts should therefore be interpreted as the available endpoint assessment, not assumed to represent every participant assigned to treatment.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastroenteritis (20.0%), fever (20.0%), pneumonia (20.0%), urinary tract infection (uti) (20.0%), vaginal abscess (10.0%).

The registry record reports serious adverse event counts for both groups among 10 participants at risk in each group. Serious adverse events affected 6 participants in the extended-release tacrolimus group and 6 in the immediate-release group. Other adverse events affected 4 and 7 participants, respectively. Deaths are reported as 0 in each group. These figures are descriptive registry counts; the record does not provide a statistical comparison of safety outcomes.

The registry also lists serious adverse event terms with percentages: gastroenteritis, fever, pneumonia, and urinary tract infection (UTI) at 20.0% each; vaginal abscess and transplant pyelonephritis at 10.0% each. The registry record does not provide further detail in this summary about the event-level data behind those terms. The listed percentages should not be treated as comparative risks or as evidence that a particular treatment caused an event.

In general, safety counts depend on how events are defined, collected, attributed, and grouped. Counts of participants affected are not necessarily the same as counts of individual events, because a participant may experience more than one event. The registry record does not report additional details needed to characterize timing, severity beyond the serious classification, attribution, or exposure-adjusted rates. These figures describe what was posted and do not establish a safety advantage or disadvantage.

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

The result establishes that biopsy-proven acute rejection was recorded for 1 participant in the extended-release tacrolimus group and 2 in the immediate-release group among participants assessed for the primary endpoint. The group sizes reported for that outcome are 8 and 10. This is a descriptive comparison of observed counts; it is not an estimate with reported precision.

The result does not establish that the treatments are equivalent, that they are different, or that either formulation changes rejection risk. The stated primary question uses the term comparable, but a claim of comparability requires more than observing similar-looking counts. In general, it requires a defined margin for an acceptable difference and an analysis that evaluates the uncertainty relative to that margin. The registry record does not report such a margin or analysis.

It also does not establish that the result applies to all kidney transplant recipients. The study focuses on HLA-sensitized recipients, and the primary outcome population consists of participants who completed their 12-month visit. The registry record does not report enough detail to assess how the assessed participants compare with those not represented in the endpoint count, or how broadly the findings can be generalized.

The study title and summary identify donor-specific antibodies, kidney function, and donor-derived cell-free DNA as outcomes of interest. The primary result is acute rejection, not a complete account of those other outcomes. The registry record does not report their comparative analysis results in the registry record for this result. No conclusion about antibody suppression, eGFR, or cell-free DNA should be inferred from the rejection counts.

The most defensible reading is therefore limited: the record documents the endpoint counts in the assessed groups, while leaving the comparative effect, its precision, and the handling of missing outcomes unreported. Those omissions prevent a firm statistical conclusion about the primary comparison.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between an observed result and an inferential conclusion. Randomization is an important design feature, but the value of a randomized comparison also depends on transparent reporting of the analysis population, effect estimate, and uncertainty. The registry record identifies a randomized, open-label, parallel-group pilot trial, yet its posted primary result consists of event counts without an inferential comparison.

The endpoint is a clinically interpretable event, but sparse event counts can make comparative estimates uncertain. In general, the precision of an estimate depends on the amount of information in the data, not only on the apparent direction of the observed counts. Reporting a confidence interval and an analysis method would help readers distinguish a potentially meaningful difference from variation that the available data cannot resolve. Neither is reported for this primary comparison.

The trial also highlights the importance of defining the population behind a result. The record says the primary assessment included participants who completed the 12-month visit and reports endpoint group sizes of 8 and 10, while enrollment is listed as 20. Without details about missing outcomes and analysis populations, readers cannot determine how the endpoint counts relate to all randomized participants.

Finally, the registry describes several secondary outcomes alongside the primary rejection endpoint. A clear multiplicity strategy and a prespecified analysis plan would help readers interpret a collection of outcomes without overemphasizing isolated findings. The registry record does not report those plans. These limitations do not erase the descriptive information, but they define what can and cannot be concluded statistically from it.

15. 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.

This is a pilot trial with enrollment listed as 20, and the primary outcome was assessed among participants who completed their 12-month visit. The endpoint group sizes reported are 8 for extended-release tacrolimus and 10 for immediate-release tacrolimus. The registry record does not report why all enrolled participants are not represented in those assessment counts or whether missingness differed by treatment group.

The primary outcome is posted as event counts, without a comparative effect estimate, confidence interval, or hypothesis test. The record identifies the two-arm binary comparison as missing or not estimable and lists no posted analyses. Consequently, the precision and statistical uncertainty of the between-group comparison cannot be evaluated from the registry record.

The trial was open-label, and the registry record does not report whether biopsy interpretation was masked, how rejection events were adjudicated, or the detailed operational definition used. It does not report the randomization sequence method, allocation concealment, adherence, or treatment deviations. These details could matter when evaluating the risk of bias, but their absence should not be filled with assumptions.

The registry record does not report a sample-size justification, original power calculation, multiplicity plan, or statistical analysis plan. It also does not report the comparative results for the listed secondary outcomes in the registry record. The trial's stated focus on antibody suppression therefore cannot be assessed from the primary rejection count alone. These reporting gaps limit conclusions about comparative efficacy, precision, and generalizability.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Comparison of Tacrolimus Extended-Release (Envarsus XR) to Tacrolimus Immediate-Release in Human Leukocyte Antigen (HLA) Sensitized Kidney Transplant Recipients — NCT04225988.
• Registry record last updated 2024-07-10; status last verified 2024-06.
• Results first posted 2024-07-10.
• 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.

19. Record Summary

NCT04225988 is a completed Phase 4 randomized, open-label, parallel-group pilot trial comparing extended-release tacrolimus, Envarsus XR, with immediate-release tacrolimus in HLA-sensitized kidney transplant recipients. Both groups also received standard-dose mycophenolate and prednisone for maintenance immunosuppression. Enrollment is listed as 20; the study started on 2020-01-09 and reached primary completion on 2023-07-11.

The primary outcome was biopsy-proven acute rejection within 12 months of transplant among participants who completed their 12-month visit. The registry reports 1 affected participant among 8 assessed in the extended-release group and 2 among 10 assessed in the immediate-release group. No inferential comparison is posted, and the registry record identifies the binary comparison as missing or not estimable. Four secondary outcomes are listed, but their comparative analyses are not reported in the registry record. The posted primary result supports a descriptive account of event counts, not a conclusion about comparative effect or precision.