Envarsus Neurotoxicity Burden in Liver Transplant Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Envarsus Neurotoxicity Burden in Liver Transplant Patients (NCT03823768), a randomized phase 4 study. The primary outcome is Change in Neurotoxicity Burden.

2. Clinical Question

The registry lists the study as completed and gives an enrollment of 30. The posted endpoint results are medians and interquartile ranges. They describe the change within each arm, but do not by themselves establish whether the arms differed. A between-arm estimate and its uncertainty, along with a statistical test, are not reported in the registry record. The clinical question should therefore be separated from the information available to answer it: the study was designed around a comparison of treatment strategies, while the posted primary results give arm-specific summaries.

3. Trial Design

This was a randomized, parallel-group, unmasked phase 4 study sponsored by the Medical University of South Carolina. The registry lists a total enrollment of 30 and a completed status. The recorded study start date is 2020-01-31, and the primary completion date is 2023-04-30. The two groups were described as a control arm receiving immediate-release tacrolimus and an intervention arm receiving Envarsus.

The control regimen was immediate-release tacrolimus twice daily for 6 months. The intervention regimen was Envarsus daily for 6 months. The registry describes Envarsus as once daily in the brief summary and official title. The primary endpoint timeframe was 6 months. The posted outcome gives an arm size of 15 for each group. These are the sizes associated with the arm-level result; the registry does not describe the number contributing to each particular measurement or whether any participants were excluded from the endpoint analysis.

Randomization helps address systematic differences between treatment groups at assignment, but the record does not report the randomization sequence method, allocation concealment, stratification, or procedures for maintaining treatment assignment. Masking is listed as none. Consequently, participants and study personnel were not masked according to the registry entry. The record does not explain whether endpoint assessment was performed by an independent assessor or whether any other safeguards against measurement or expectation effects were used.

The study compares treatment regimens rather than isolated dosing frequencies: the arms differ in the named medication formulation and dosing schedule. The registry does not provide further details about conversion procedures, dose adjustment, adherence, or concomitant care. The record lists one primary outcome measure and no posted secondary outcome measures. It lists no analyses. The statistical analysis plan, including any prespecified between-group estimator, adjustment strategy, or handling of repeated measurements, is not reported in the registry record.

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

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 Change in Neurotoxicity Burden, measured over 6 months.

The primary endpoint was change in neurotoxicity burden from baseline to 6 months, measured with a composite Patient Global Impression of Improvement score, or PGI-I. The registry describes a transition scale made from four questions, each with seven response choices. The total score ranges from 4 to 28, with higher values representing a worsening condition. A score of 16 indicates no overall change; scores of 15 or lower indicate improvement, and scores of 17 or higher indicate worsening. The scale endpoints are 4, described as very much better, and 28, described as very much worse. The registry states that a relative change of 2 points would be considered a significant change from baseline.

A global impression measure is intended to represent a person’s overall assessment of change rather than a single symptom or laboratory value. Combining the four responses into one score can summarize several aspects of perceived neurologic burden. That summary is useful for a broad patient-centered outcome, but it also compresses information: equal totals may arise from different response patterns across the questions. The registry record does not report the questions themselves, validation details for this population, or how the score was calculated if responses were incomplete.

The posted results use the median change and interquartile range. A change score is interpreted relative to baseline; a negative median change is directionally consistent with improvement under the registry’s description that higher scores mean worsening. The arm summaries do not state the proportion of participants who improved or worsened, and they do not provide a direct comparison between treatments.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the median describe?

The median is the middle of an ordered set of observations. It is a measure of location that is less affected by unusually high or low values than the arithmetic mean. For a change score, it gives a concise description of the central observed change among the values included in the summary. In this trial, the registry reports a median change for each arm rather than a mean change. This is a descriptive choice; it does not, on its own, estimate the randomized treatment contrast.

The median can be useful when a score’s distribution is skewed or contains extreme values. It also has limitations. It does not describe every participant’s experience, and it can be the same for groups with different distributions. For this reason, the median is usually interpreted alongside a measure of spread. Here, the registry identifies the spread as an interquartile range. The record does not say why this summary approach was selected or describe the distribution of the underlying scores.

What does an interquartile range show?

The interquartile range describes the middle half of the observed values, bounded by the lower and upper quartiles. It indicates how dispersed the central observations are, but it does not show the full range of responses. The reported values from -13.5 to -0.25 for the control arm and -9.5 to -0.5 for the Envarsus arm are interquartile ranges, not confidence intervals. A confidence interval instead represents uncertainty around an estimated quantity, under a specified method and assumptions. No confidence interval for a between-arm effect is posted.

Overlap or non-overlap between interquartile ranges is not a substitute for a formal comparison. The interquartile ranges summarize participant-level variation within each arm. They do not directly quantify the uncertainty in the difference between arms, and they do not answer whether any observed contrast could plausibly be due to chance under a specified statistical model.

Why does the scale’s direction matter?

Statistical interpretation must follow the endpoint definition. The registry says higher PGI-I values represent a worsening condition, and that a score of 16 indicates no overall change. It describes scores of 15 or lower as improvement and scores of 17 or higher as worsening. Thus, a negative change is directionally consistent with improvement in score. That directional interpretation does not establish that all participants improved or that one regimen produced greater improvement. The arm medians do not provide individual response categories or a comparative estimate.

The registry also states that a relative change of 2 points would be considered significant from baseline. A threshold for meaningful change and a statistical test of a treatment contrast answer different questions. A threshold can help interpret the scale’s magnitude, while a hypothesis test evaluates data under a specified model. Neither can be substituted for the other. The record does not explain the threshold’s derivation or report a test of the between-arm contrast.

What would a randomized comparison require?

In a randomized trial, the principal comparative question concerns outcomes between assigned groups. An analysis might compare change scores, compare follow-up scores while accounting for baseline, or use another prespecified approach. The appropriate method depends on the protocol, outcome properties, and missing-data plan. The registry record does not identify the chosen estimator or model. It lists no analyses and indicates that values are missing or not estimable for a two-arm comparison for this endpoint.

Without a comparative estimate, its uncertainty, and the method used to obtain it, arm-level medians should remain descriptive. A direct comparison should also account for the randomized design and the fact that participants are observed within assigned groups. The registry record does not report covariate adjustment, repeated-measure methods, or any sensitivity analyses. These details are not available for assessing robustness.

How should planning calculations be understood?

The registry’s planning illustration is described as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The effect to detect is stated as a fraction of the observed effect. Such calculations are illustrations of sample sizes under specified assumptions, not evidence that a trial had a particular probability of detecting an effect after it was conducted. They are not observed power and do not replace the trial’s own design justification. The registry record does not report the original sample-size justification or its assumptions.

A planning calculation that uses an observed effect is especially dependent on the chosen effect estimate and assumptions. The available registry entry does not post a usable two-arm effect estimate for this endpoint, and it gives no sample-size calculation values in the trial description. The registry record does not report whether an interim analysis occurred or whether the study design changed. No conclusions about those matters can be drawn from the arm summaries.

More generally, statistical methods should be judged by whether they match the scientific question, outcome scale, and data structure, and whether they were prespecified and reported clearly. Randomization is an important design feature, but it does not supply the missing analysis details. The posted medians and interquartile ranges allow descriptive interpretation; they do not provide the inferential evidence needed to quantify a treatment difference.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and no posted secondary outcome measures. It lists no analyses. The record therefore does not report a multiplicity strategy, such as a hierarchy of outcomes or an adjustment for multiple statistical tests. With only the listed endpoint available, it is not possible to determine whether other outcomes or analyses were planned but not posted. The statistical analysis plan and any prespecified decision rules are not reported in the registry record.

Missing-data handling is also not described. The registry does not report the number of participants with baseline and 6-month measurements, reasons for missing endpoint values, or methods for handling incomplete responses to the four PGI-I questions. The arm results each list 15 participants, but that alone does not establish that all randomized participants contributed complete endpoint data. The record does not describe imputation, complete-case analysis, sensitivity analyses, or any other missing-data approach.

The analysis population is not specified. The registry does not say whether the endpoint summaries use all randomized participants, participants who received treatment, participants who completed follow-up, or another defined group. It also does not report exclusions after randomization or adherence information. These omissions matter because the interpretation of a randomized comparison depends on knowing how participants were included and how missing outcomes were addressed.

These are reporting gaps, not evidence that any particular method was or was not used. They limit assessment of the risk of bias and the reliability of a comparative conclusion. The posted results should therefore be read as descriptive arm-level summaries, without assumptions about unreported analyses, populations, or missing-data procedures.

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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: acute rejection (6.7%).

The registry reports serious adverse events for each arm. In the immediate-release tacrolimus arm, 0 serious adverse events were recorded among 15 at risk. In the Envarsus arm, 1 serious adverse event was recorded among 15 at risk. The record identifies Acute Rejection as the top serious adverse event term and gives 6.7%. No deaths were reported in either arm.

These figures describe events recorded in the registry; they do not establish that a treatment caused an event. The record does not provide event-level timing, participant-level detail, adjudication information, or an analysis comparing serious adverse event risk between arms. A single observed event in one arm and none in the other is descriptive information, not a reliable basis for estimating a difference in safety. The registry does not report a statistical test or uncertainty interval for these safety figures.

The serious adverse event counts should also be kept separate from the primary neurotoxicity endpoint. The primary endpoint is a change in a composite patient-reported score; the safety figures concern serious adverse events. The registry lists 0 other adverse events in each arm, but the available record does not provide further details about adverse event collection or duration beyond the treatment regimen and primary endpoint timeframe. Safety interpretation is therefore limited to the recorded counts and term.

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

The posted primary results show negative median change scores in both arms: -5.0 with an interquartile range of -13.5 to -0.25 for immediate-release tacrolimus, and -4.0 with an interquartile range of -9.5 to -0.5 for Envarsus. Since the registry defines higher PGI-I values as worse, these negative changes point toward lower scores relative to baseline. This is a description of the observed arm summaries, not proof that every participant improved.

The results do not establish that Envarsus is better, worse, or equivalent to immediate-release tacrolimus. The record provides no two-arm estimate, confidence interval, or statistical test for the primary endpoint. A comparison cannot be inferred by subtracting the medians or judging the interquartile ranges. The registry itself notes that values are missing or not estimable for a two-arm comparison for this endpoint.

The endpoint description’s 2-point criterion is stated as a significant change from baseline. It should not be confused with a statistically significant difference between randomized treatment groups. The registry does not report how this criterion was established or whether either arm’s change met it according to a prespecified analysis. Nor does the outcome report how many participants improved, stayed the same, or worsened.

The trial was randomized, which is relevant to causal comparisons, but the posted summaries alone do not use that design to estimate a treatment effect. Interpretation is further constrained by the absence of reported analysis methods, analysis populations, and missing-data procedures. The results cannot answer whether the hypothesized lower rate of neurologic side effects with Envarsus was observed, because the posted endpoint is a score change and no comparative analysis is reported.

These limitations do not erase the descriptive information in the registry, and they do not imply that the treatment regimens had identical effects. They mean that the available record does not quantify the difference between them with enough inferential detail to support a comparative conclusion. The safety counts likewise describe recorded events without establishing causation or comparative risk.

13. Why This Trial Matters Statistically

This trial raises a statistical question common in clinical research: how to turn a patient-centered change measure into a clear comparison between randomized groups. The PGI-I composite is intended to capture a global impression of change in neurotoxicity burden. Its direction and thresholds give clinical context to the score, but the scientific comparison still requires an explicit estimate of how outcomes differ between arms and how uncertain that estimate is.

Reporting medians and interquartile ranges can be informative when the outcome distribution is not well represented by a mean and standard deviation. However, arm-specific summaries do not automatically answer a randomized treatment question. A comparative estimate, its uncertainty, and a transparent account of the analysis population would make it possible to distinguish descriptive changes from evidence about differences between regimens.

The unmasked design is also statistically relevant because the primary measure is based on patient impressions. The registry identifies the study as unmasked but does not describe additional safeguards or assessment procedures. This does not demonstrate that the outcome was biased, but it makes clear reporting of outcome collection and analysis particularly important.

The study is listed as completed, yet the registry record contains no posted analysis and no estimable two-arm comparison for the primary endpoint. That distinction matters: completion status and arm-level results do not by themselves establish that the planned scientific comparison has been reported. A complete interpretation would need the prespecified analysis, information about missing outcomes and participant inclusion, and a direct contrast with uncertainty. Without those elements, the main statistical value of the posted result is descriptive rather than comparative.

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.

Several trial-specific limitations restrict interpretation of the posted results. The registry identifies the study as randomized but does not describe sequence generation, allocation concealment, or any stratification. It lists masking as none. Because the primary endpoint is a patient-reported global impression, the absence of masking may be relevant to reporting and assessment, although the registry does not provide evidence about whether it affected responses.

The record does not give participant characteristics, eligibility criteria, baseline neurotoxicity burden, or details of the conversion process. It therefore does not allow assessment of how comparable the groups were at baseline or how broadly the results might apply to other liver transplant recipients. Treatment adherence, dose adjustments, concomitant therapies, and protocol deviations are also not reported.

The outcome information is limited to the median change and interquartile range for each arm. No direct comparison, confidence interval, or statistical test is posted, and the registry notes that a two-arm comparison is not estimable for this endpoint. The record also does not describe the endpoint analysis population, missing-data handling, or the number with complete follow-up. These omissions prevent assessment of whether the arm summaries represent all randomized participants.

The registry gives a score range and interpretation but does not report the individual questions, measurement validation in this study population, or handling of incomplete responses. It also does not explain the basis of the stated 2-point criterion. The safety information is limited to event counts and a top serious adverse event term; event-level context and comparative analyses are not reported.

Finally, the registry record does not report the original sample-size justification, a statistical analysis plan, or whether interim analyses occurred. These items should be treated as unreported rather than assumed absent. Together, the limitations mean that the posted information supports a narrow descriptive reading, not a definitive comparative assessment.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Envarsus Neurotoxicity Burden in Liver Transplant Patients — NCT03823768.
• Registry record last updated 2025-03-30; status last verified 2025-03.
• Results first posted 2024-06-27.
• 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 record describes a completed, randomized, unmasked, parallel-group phase 4 trial of Envarsus versus immediate-release tacrolimus in liver transplant recipients. Enrollment is listed as 30. The control regimen was immediate-release tacrolimus twice daily for 6 months; the intervention regimen was Envarsus daily for 6 months. The primary endpoint was change in neurotoxicity burden at 6 months, measured with a composite PGI-I score.

The reported median change was -5.0 in the control arm and -4.0 in the Envarsus arm, with interquartile ranges of -13.5 to -0.25 and -9.5 to -0.5, respectively. Each arm result lists 15 participants. The record does not report an estimable two-arm comparison or a statistical analysis for the endpoint. Serious adverse event counts were 0 in the control arm and 1 in the Envarsus arm; no deaths were reported. The posted information is descriptive and does not establish a comparative treatment effect.