Envarsus on the Effect of Total Tacrolimus Dose/Trough Level Ratio on Renal Function (eGFR) in Kidney Transplantation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Envarsus on the Effect of Total Tacrolimus Dose/Trough Level Ratio on Renal Function (eGFR) in Kidney Transplantation (NCT03511560), a randomized phase 4 study. The primary outcome is Mean C/D Ratio.

2. Clinical Question

3. Trial Design

This was a Phase 4, randomized, open-label, parallel-group trial sponsored by Columbia University. The registry records an enrollment of 50 and a completed status. The recorded study start date is 2018-07-26, and the primary completion date is 2020-07-17. The study description characterizes it as prospective and says participants would be followed for up to 1 year during the open-label study period.

The two regimens differed in formulation and dosing frequency. Envarsus XR was an extended-release tacrolimus tablet administered once daily, with an initial weight-based dose of 0.12 mg/kg. Immediate-release tacrolimus was administered twice daily. For both groups, later dosing and monitoring were guided by clinical judgment, and the arm descriptions specify a minimum whole-blood tacrolimus concentration target of at least 8 ng/mL. These are protocol descriptions; they do not establish the doses participants actually received or the concentrations they achieved.

Randomization can help balance baseline characteristics across groups on average, but the allocation sequence, concealment procedures, stratification factors, and baseline characteristics are not reported in the registry record. Masking was listed as none. As a result, participants and clinical staff could know the assigned regimen, and the record does not describe masking of outcome assessment or data analysis.

The registry lists secondary outcomes of mean serum creatinine level, patient survival rate, graft survival rate, and number of rejection episodes. The descriptions, analysis results, and complete outcome-specific denominators are not reported in the registry record. Although the record gives an enrollment figure, that figure alone does not show how many participants contributed data to each outcome or how missing follow-up was handled.

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:

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 C/D Ratio, measured over Every Month for up to 1 year.

The primary endpoint, mean C/D ratio, is a continuous measure intended to describe tacrolimus exposure in relation to the total daily dose. For each collection date, the registry defines the ratio as the blood tacrolimus trough concentration in ng/mL divided by the corresponding total daily tacrolimus dose in mg. A higher ratio would mean a higher trough concentration relative to the daily dose; it should not be read as a direct measure of kidney function.

The registry says this measure was assessed every month for up to 1 year and identifies the reported summary as a mean with standard deviation. Repeated measurements can describe how the ratio behaves over follow-up, while a group mean provides a summary of the observed values. The standard deviation describes spread among observations; it is not a measure of uncertainty in the estimated mean. The record does not report a primary-outcome estimate for either group, a between-group contrast, a confidence interval, or a test result.

The trial description also says kidney function would be examined using estimated glomerular filtration rate (eGFR), and it mentions one-year kidney outcomes including graft loss and patient death. However, the registered primary outcome is mean C/D ratio, not eGFR. The available record does not report an eGFR result or establish how the stated kidney outcomes relate analytically to the primary endpoint. The C/D ratio can therefore be described as a pharmacologic measure, but the registry information does not show whether it was associated with kidney function in this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a randomized, parallel-group design and a continuous primary outcome summarized as a mean with standard deviation. It does not report the statistical methods used to analyze that outcome. The explanations below are general statistical context, not a description of an analysis confirmed in the registry record.

What does randomization contribute?

In general, random assignment aims to make treatment groups comparable with respect to both measured and unmeasured baseline factors, on average. It supports a causal interpretation of a between-group contrast when the trial is conducted and analyzed appropriately. Randomization does not guarantee balance in a particular trial, especially when the groups are modest in size, and it does not eliminate bias from missing outcomes, deviations from assigned treatment, or outcome measurement. The registry record does not report the allocation sequence, concealment method, baseline comparison, or analysis population, so those features cannot be assessed from the record.

What does a mean and standard deviation describe?

For a continuous measure, the mean is a measure of the central value, while the standard deviation describes how spread out observed values are around that mean. They answer different questions. The standard deviation is not the standard error and does not, on its own, quantify the precision of a mean estimate. Precision depends on the amount of information in the analysis and on the variability and structure of the observations. The record names the mean and standard deviation as the endpoint summary but does not report their observed values.

Why do repeated measurements matter?

Measurements taken from the same participant over time are generally correlated: one participant's readings may resemble one another more than readings from different participants. General methods for repeated measures account for that dependence rather than treating every measurement as independent. Possible approaches include modeling changes over time or estimating a group contrast across repeated observations, but the appropriate choice depends on the scientific question and analysis plan. The registry specifies monthly measurement for up to 1 year but does not report a longitudinal model, a time-point-specific contrast, a summary across visits, or a method for handling within-participant correlation.

The timing and availability of measurements also matter. Participants may have different amounts of follow-up, and observations may be missing for reasons related to health, treatment, or study participation. Analyses that use only complete records can differ from analyses that use all available repeated measurements under stated assumptions. The record does not report missing-data counts, reasons for missingness, imputation methods, or sensitivity analyses. It is therefore not possible to determine how incomplete follow-up affected the primary-outcome estimate.

How should uncertainty be assessed?

In general, a confidence interval gives a range of values compatible with the data and the assumptions of the analysis. Its width communicates precision, while its location describes the estimated effect and the values that remain plausible under the method. A p-value addresses compatibility with a specified null hypothesis under model assumptions; it does not measure the probability that the null hypothesis is true or the size of an effect. For this trial, the primary-outcome estimate, confidence interval, and p-value are not reported in the registry record, so neither effect size nor inferential uncertainty can be evaluated.

What is the role of the analysis model?

A statistical model translates observations into an estimate and its uncertainty. For a continuous outcome, a model might account for baseline values, repeated observations, or other prespecified factors. Adjusted and unadjusted estimates can differ, and their interpretation depends on the variables and assumptions used. The record does not report a model, covariate adjustment, diagnostic checks, or a prespecified primary contrast. No model should be inferred from the fact that the trial was randomized or that the outcome is continuous.

The registry record lists zero analyses. That does not establish that no analyses were conducted outside the registry; it means that analyses are not recorded there. Likewise, the record describes a sample-size planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are planning exercises under stated assumptions, not observed power and not evidence about the precision or result of the completed trial. No sample-size illustration can substitute for a reported outcome estimate and its uncertainty.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and several secondary outcomes, while the primary C/D ratio is scheduled for measurement every month for up to 1 year. Considering multiple outcomes or multiple time points can create multiplicity: the more comparisons examined, the greater the chance of finding an apparently notable result by chance when each is interpreted separately. General approaches include defining one primary contrast in advance, adjusting inference for a family of comparisons, or clearly labeling additional analyses as exploratory. The registry record does not report a multiplicity strategy, a hierarchy among outcomes, or which time point or summary was designated for the primary comparison.

The record also does not report an analysis plan, outcome-specific analysis populations, or a participant flow account. It is therefore not clear which participants were included in each analysis, how adherence or treatment changes were handled, or whether the analysis followed assigned treatment. These details matter because analyzing participants according to assigned group and analyzing them according to treatment received answer different questions.

Missing data can affect both the estimate and its uncertainty, especially when follow-up is repeated. The registry does not report the amount or pattern of missing primary-outcome observations, reasons for missingness, imputation, or sensitivity analyses. Without those details, the assumptions behind any potential analysis cannot be assessed. Results for eGFR, creatinine, survival, graft survival, and rejection episodes are also not reported in the registry record, so completeness and analysis methods for those outcomes are unknown.

The registry record lists zero analyses. It does not report whether analyses were conducted elsewhere or whether the registry entry was updated after analysis. Accordingly, multiplicity control, handling of missing data, and the analysis populations remain not reported in the registry record.

11. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event record lists 0 participants with serious adverse events among 24 at risk in the immediate-release group and 0 among 21 at risk in the Envarsus XR group. It lists other adverse events affecting 8 participants in the immediate-release group and 6 in the Envarsus XR group, with the same at-risk counts recorded for those entries. The listed death count is 0 in each group.

These are counts, not a complete comparison of risks. The registry does not report the types, timing, severity, or duration of the other adverse events, and it lists no top serious adverse-event terms. The at-risk figures attached to the safety entries also do not establish the analysis population for the primary endpoint or other outcomes. No comparative safety estimate, confidence interval, or statistical test is reported in the registry record.

A count of 0 serious events in the recorded groups does not demonstrate that serious events cannot occur or that the regimens have equivalent safety. Counts can be affected by the amount and completeness of follow-up, and the record does not provide sufficient detail to evaluate those factors. The death entries are safety-record counts and should not be interpreted as a full patient-survival analysis, which is listed separately as a secondary outcome.

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

The trial addresses a focused pharmacologic question: how the tacrolimus trough concentration relative to total daily dose compares between a once-daily extended-release regimen and a twice-daily immediate-release regimen in a kidney-transplant setting. The registry identifies randomization and an open-label, parallel-group design, and it defines the primary C/D ratio. Those details clarify the intended comparison, but they do not provide its result.

The primary endpoint is not itself an eGFR measure, a graft-survival measure, or a patient-survival measure. A difference in C/D ratio, if one were reported, would describe the measured ratio; it would not alone establish a difference in kidney function, rejection, graft loss, or death. Such conclusions would require the relevant outcome data and analyses. The registry lists several of these outcomes, but their results are not reported in the registry record.

The record does not report group-specific C/D ratio means, a between-group estimate, confidence intervals, or a p-value. It therefore cannot show whether the observed groups differed, how large any difference might have been, or how precisely it was estimated. Missing results should not be read as proof of no difference, as proof of benefit, or as evidence that the treatments are interchangeable.

The design description and dosing targets are also not outcome findings. They specify how the regimens were intended to be administered and monitored, but do not show adherence, achieved concentrations, or actual dose patterns. The open-label status means masking was not used; its potential influence on care, measurement, and reporting cannot be assessed from the registry information alone.

The appropriate interpretation is therefore limited: the registry records a randomized trial comparing two tacrolimus dosing regimens and identifies the C/D ratio as its primary measure, but it does not report the comparative primary result. The listed safety counts provide limited descriptive information and do not resolve comparative safety. Conclusions about clinical outcomes or the relative performance of the regimens require outcome results and analysis details not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it separates a dosing-related pharmacologic measure from clinical outcomes. The C/D ratio expresses trough concentration relative to total daily dose, while the study description also names eGFR and one-year kidney outcomes. Keeping these endpoints distinct is important: a measure of drug concentration relative to dose does not automatically answer whether kidney function or patient outcomes differ.

The randomized parallel-group design provides a framework for comparing the two regimens. The open-label design is also relevant to interpretation because participants and treating clinicians could know the assigned regimen. Knowledge of assignment can influence treatment decisions or outcome assessment, depending on the endpoint and study procedures. The registry does not describe masking of outcome assessment or how this possibility was addressed.

Repeated monthly measurement makes the analysis question more complex than a single comparison of independent observations. A sound analysis needs to define what group difference is being estimated over follow-up and account for the relationship between measurements from the same participant. The record states the measurement schedule but does not report the analysis method or the chosen primary contrast. That makes the planned question clearer than the statistical implementation.

The record also illustrates why a trial registration and a result report serve different purposes. Registration describes intended design and outcomes, whereas outcome estimates and uncertainty are needed to judge what the trial observed. Here, the registry records the primary endpoint and design but does not report the comparative primary result. Without estimates and uncertainty, readers cannot assess the size or precision of a possible difference, regardless of the trial's randomized design.

Finally, the registry lists safety counts and several clinical secondary outcomes, but does not provide a complete comparative analysis of them. Reading each outcome in its proper role prevents a pharmacologic measure, a sparse event count, or an unreported endpoint from being mistaken for a broader conclusion about clinical effects.

14. 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.

A major limitation for interpreting this record is that it does not report the primary outcome values or a between-group analysis. The endpoint is described, but the absence of an estimate, uncertainty interval, and inferential result prevents assessment of effect direction, size, and precision. This is a limitation of the registry information available for interpretation and does not establish what may have been reported elsewhere.

The registry indicates monthly C/D ratio measurement for up to 1 year but does not specify the primary time point or longitudinal summary used for analysis. It also does not report how repeated measurements were modeled, how missing observations were handled, or which participants contributed to the primary analysis. These omissions limit assessment of the estimand and the assumptions supporting any potential result.

Masking was listed as none. The registry does not describe blinded outcome assessment or procedures to reduce the influence of treatment knowledge. Allocation concealment, baseline characteristics, adherence, treatment changes, and actual tacrolimus concentrations are also not reported in the registry record. As a result, the record does not permit evaluation of how closely the observed treatment experience followed the intended regimens or whether other differences between groups might matter.

The record includes an enrollment figure of 50, while safety entries list at-risk counts of 24 for immediate-release tacrolimus and 21 for Envarsus XR. Those figures refer to different registry entries and should not be treated as a complete participant-flow account. Reasons for the recorded safety populations, outcome-specific denominators, withdrawals, and follow-up completeness are not reported.

Finally, eGFR and several clinical outcomes are mentioned or listed, but their results and analysis details are not reported in the registry record. The safety entries give limited counts without event descriptions or a comparative analysis. These gaps restrict conclusions about both clinical outcomes and safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Envarsus on the Effect of Total Tacrolimus Dose/Trough Level Ratio on Renal Function (eGFR) in Kidney Transplantation — NCT03511560.
• Registry record last updated 2024-07-17; status last verified 2024-06.
• Results first posted 2024-07-17.
• 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.

18. Record Summary

The registry describes NCT03511560, a completed Phase 4 randomized, open-label, parallel-group trial sponsored by Columbia University. It compares once-daily Envarsus XR with twice-daily immediate-release tacrolimus in a kidney-transplant setting. The recorded enrollment is 50; the study start date is 2018-07-26, and the primary completion date is 2020-07-17.

The primary outcome is mean C/D ratio, defined as the blood tacrolimus trough concentration divided by the corresponding total daily tacrolimus dose, with measurement planned every month for up to 1 year. The registry lists eGFR in the study description and lists serum creatinine, patient survival, graft survival, and rejection episodes as secondary outcomes.

Comparative primary-outcome estimates, analysis methods, and results for the listed clinical outcomes are not reported in the registry record. Safety entries list 0 serious adverse events and 0 deaths in each group, with other adverse-event counts of 8 for immediate-release tacrolimus and 6 for Envarsus XR. These entries are descriptive and do not provide a complete comparative analysis.