Crossover Study to Compare PK of Once Daily LCP-Tacro Tablets to Generic Tacrolimus Capsules Twice Daily.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Crossover Study to Compare PK of Once Daily LCP-Tacro Tablets to Generic Tacrolimus Capsules Twice Daily. (NCT01962922), a randomized phase 3 study. The primary outcome is Evaluation of AUC(0-24) for Envarsus XR and IR-Tac.

2. Clinical Question

This is a pharmacokinetic comparison, not a comparison of transplant outcomes or a test of clinical benefit. AUC(0-24) represents exposure across the 24-hour sampling interval, calculated from measured whole-blood tacrolimus concentrations using actual sampling times. The record reports arithmetic means and standard deviations for each treatment and a mean difference for Tacrolimus - IR relative to Envarsus XR.

The result is specific to the population and study context recorded: stable African-American renal transplant patients in a prospective, randomized, open-label, single-center crossover study. The record does not report a broader population definition or establish that the result applies to other groups. The main statistical question is how precisely the posted mean difference estimates the contrast in exposure, not whether one regimen improves health outcomes.

3. Trial Design

The registry record describes a prospective, randomized, open-label, single-center study with a two-sequence, three-period crossover model. It is listed as Phase 3 and completed. The record lists enrollment of 50 and gives a study start of 2013-11 and primary completion of 2015-07. The study compared once-daily extended-release LCP-Tacro, described as Envarsus XR, with generic tacrolimus capsules administered twice daily, described as Tacrolimus - IR.

A crossover design means participants receive more than one treatment over successive study periods, rather than remaining in only one treatment group throughout. The stated two-sequence, three-period structure indicates that treatment order was organized into sequences and periods. Random allocation is reported, while masking is listed as none; the design was therefore open label. The registry record does not report the sequence details, period-specific treatment order, washout procedures, or how possible period or sequence effects were handled in the statistical analysis.

The primary endpoint was evaluated at Day 7 using the PK population of 46. The record reports 23 observations for each treatment in the primary outcome summaries. Those treatment-specific summary counts do not explain the individual crossover data structure or establish how paired observations were incorporated into the reported contrast. The enrollment figure and the PK population are distinct record entries; the reason for the difference is not reported in the registry record.

The record lists nine outcome measures and no posted secondary outcomes. It lists no analyses in the registry analysis count, although it does post a primary outcome comparison. Details of the protocol's original design assumptions, including any sample-size justification, are 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.

PK Portion Day 7

Reasons for not completing this period:

PK Portion Day 14

PK Portion Day 21

Extendion Portion (up to Month 6)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: For this outcome measure the PK population N=46 was used.

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 Evaluation of AUC(0-24) for Envarsus XR and IR-Tac, measured over Day 7.

The primary endpoint is the evaluation of AUC(0-24) for Envarsus XR and immediate-release tacrolimus at Day 7, with values expressed in ng*hr/mL. AUC is the area under the concentration-time curve: in general, it summarizes drug concentration over a defined time interval. For this outcome, whole-blood tacrolimus concentrations from the central laboratory were used, and actual sampling times were used to calculate the exposure measure. The listed nominal sampling schedule ran from pre-dose through 24 hours.

AUC is used in pharmacokinetic studies because it provides a summary of exposure across the measurement interval rather than relying on a single concentration at one time point. That is relevant when comparing regimens with different dosing schedules. The endpoint is a continuous measure, and the registry reports arithmetic means and standard deviations for the treatment summaries.

The endpoint describes drug exposure, not graft function, rejection, survival, or another clinical outcome. Although the study concerns renal transplant patients, the posted primary result cannot by itself answer questions about clinical effectiveness or safety. The record identifies Day 7 as the timeframe for the primary endpoint but does not report additional endpoint timeframes in the posted primary description.

7. Results Posted in the Registry

• Tacrolimus - IR: mean 247.90 versus 251.90 on control; difference -4.00 (95% CI -56.53 to 48.53), standardized effect d = -0.04; z-test p = 0.881.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover design change?

In general, a crossover trial measures outcomes under more than one treatment within the same participant. This can allow a treatment contrast to use within-participant information, which may reduce the influence of stable differences between participants. It also means the analysis must account for the dependence between measurements from the same participant. Period effects, sequence effects, and possible carryover are additional design considerations in general. The registry record states that this was a two-sequence, three-period crossover study, but does not report the statistical model or explain how these design features were handled.

What do the means and standard deviations describe?

The reported means are arithmetic averages of the AUC(0-24) observations for each treatment summary. The standard deviation describes how dispersed individual observations are around their group mean; it is not a measure of uncertainty in the mean difference. The reported mean and standard deviation were 251.9 and 77.78 for Envarsus XR, and 247.9 and 102.3 for Tacrolimus - IR, in ng*hr/mL. The outcome description identifies the PK population as N=46, while the two treatment summaries each report n=23. The record does not provide individual observations or further detail about the construction of those treatment summaries.

How should the mean difference be read?

The comparison reports Tacrolimus - IR relative to Envarsus XR. Its estimated mean difference is -4.0 ng*hr/mL. A negative estimate indicates that the reported Tacrolimus - IR mean was lower than the Envarsus XR mean in the posted comparison. This direction is a description of the estimate, not a clinical judgment. The registry record does not specify whether the estimate came from a paired analysis, an adjusted model, or a particular crossover model. The posted group summaries should not be used to infer an unreported method.

What does the p-value contribute?

In general, a p-value measures how compatible the observed data are with a specified null hypothesis under the assumptions of the statistical test. The unadjusted p-value is 0.881. The term unadjusted indicates that this is not presented as a multiplicity-adjusted result. The specific test, model, null hypothesis details, and analysis assumptions are not reported in the registry record. A p-value does not convey the size or clinical importance of a difference, and it is not the probability that the null hypothesis is true. The estimate and confidence interval give complementary information about magnitude and precision.

What does the confidence interval add?

In general, a confidence interval describes uncertainty around an estimate under the method's assumptions. The reported interval for the mean difference is -56.53 to 48.53 ng*hr/mL. Its inclusion of values below and above zero indicates that the data, as summarized by this interval, do not pin down the direction of the mean difference. The interval is not a range that guarantees the true value lies within it, and its validity depends on the analysis method and assumptions. The registry record does not give enough model detail to evaluate those assumptions for this crossover comparison.

Why can variability matter?

In general, greater variability makes it harder to estimate a mean precisely when other aspects of a study are unchanged. A standard deviation describes participant-level dispersion, whereas a standard error describes uncertainty in an estimate; these are not interchangeable. The posted treatment standard errors are 16.22 and 21.34. The record does not explain the method used to obtain them or whether they account for within-participant correlation. In analyses of count data, over-dispersion can make a simple model understate uncertainty; that general issue is not the basis of this continuous AUC endpoint.

What is and is not specified about the analysis?

The record specifies the endpoint, units, timeframe, summary statistics, treatment summaries, mean difference, confidence interval, and unadjusted p-value. It does not report the detailed statistical analysis plan, a model specification, assumptions checks, missing-data procedures, or treatment of sequence and period effects. It also does not report whether an interim analysis was planned or conducted. These omissions limit assessment of the precision and robustness of the posted comparison; they do not justify assuming that a particular method was or was not used.

10. Confidence Intervals and Precision

The reported mean difference for Tacrolimus - IR relative to Envarsus XR is -4.0 ng*hr/mL, with a 95% confidence interval from -56.53 to 48.53. A confidence interval is a statistical description of uncertainty around an estimate, conditional on the method and assumptions used. In general, narrower intervals indicate greater precision, while wider intervals leave a broader range of values compatible with the data and method.

This interval spans values below and above zero. It therefore does not precisely identify the direction of the mean difference. The point estimate is close to zero, but the interval includes differences that are appreciably lower or higher than that estimate. It would be incorrect to treat the interval as proof that there is no difference, or to interpret the confidence level as the probability that the true value lies in this particular interval.

The standard deviations, 77.78 for Envarsus XR and 102.3 for Tacrolimus - IR, describe variation in the treatment summaries. The standard errors are 16.22 and 21.34. These quantities have different interpretations: standard deviations describe dispersion in observations, while standard errors describe uncertainty in estimates. The record does not explain the calculation method for the standard errors or whether the confidence interval accounts for the crossover pairing.

Precision should be judged alongside the study design and analysis details. The PK population is described as N=46, with n=23 for each treatment summary, but the registry record does not give the crossover model, missing-data handling, or other analysis specifications needed to assess the interval's assumptions fully.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations use the observed effect as a reference and show participant requirements per arm for a parallel-style planning calculation. They are not the trial's original design assumptions. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The figures are participants per arm, not total events.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect and the other assumptions were correct. The 90% power column gives the corresponding planning number for a higher target chance of detection. These are design calculations, not results observed in this crossover study. This is not observed power.

For 100% of the observed effect, the illustrations give 8,105 participants per arm for 80% power and 10,850 for 90% power. For 75% of the observed effect, they give 14,409 and 19,289 participants per arm. For 50% of the observed effect, they give 32,419 and 43,399 participants per arm. These unusually large illustrations arise because the observed mean difference is small relative to the variability used in the calculation. They are mathematical planning outputs, not recommendations or a description of the original trial.

Smaller effects require more participants to distinguish them from random variation at a fixed significance level and target power. The trial's own original sample-size justification and design assumptions are not reported in the registry record. The planning display therefore should not be used to infer what the investigators planned, or to assess the trial against an undocumented target.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -4.000; pooled standard deviation σ = 90.888.
2. n = 2 × (1.96 + 0.842)² × 90.888² / -4.000² = 8,104.5, rounded up to 8,105 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -4                      # observed difference in means
sigma <- 90.887725518906                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1962922)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 8,105 (80% power), 10,850 (90% power)
 75% of observed effect: n per arm = 14,409 (80% power), 19,289 (90% power)
 50% of observed effect: n per arm = 32,419 (80% power), 43,399 (90% power)
power.t.test: 8105.5 
Simulated power at n = 8,105 per arm: 0.803 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists nine outcome measures, but no secondary outcome results are posted. It gives a primary outcome comparison and an unadjusted p-value of 0.881. It does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified strategy for controlling the chance of false-positive findings across multiple tests. The meaning of the unadjusted label should therefore remain narrow: the posted p-value is not described as adjusted for multiple comparisons.

The primary outcome description identifies the PK population as N=46. Each treatment summary reports n=23. Enrollment is listed as 50, but the reason the PK population differs from enrollment is not reported in the registry record. The record does not say whether exclusions, incomplete sampling, protocol deviations, or another reason account for this difference; none should be assumed.

Missing-data methods are not reported in the registry record. There is no description of how missing concentrations or incomplete profiles were handled, whether imputation was used, or whether sensitivity analyses were conducted. The record also does not state how the crossover data were modeled, including whether within-participant pairing, period effects, or sequence effects were incorporated.

The analysis population and the published summary counts are important context for interpreting the result, but they do not resolve the absent methods details. The registry analysis count is 0, and the registry record does not provide an analysis plan or further analysis descriptions. An interim analysis plan or conduct is also not reported in the registry record.

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: cellulitis (2.0%), corona virus infection (2.0%), gastroenteritis viral (2.0%), otitis media (2.0%), pneumonia (2.0%).

The registry lists serious adverse events for 50 participants at risk in each treatment group. Serious adverse events affected 3 participants in the Envarsus XR group and 4 in the Tacrolimus - IR group. Other adverse events affected 23 participants in the Envarsus XR group and 22 in the Tacrolimus - IR group; the record also lists 50 at risk in each group for these events.

These are group-level counts as reported in the adverse-event record. They should not be interpreted as a paired comparison or as evidence of a treatment effect. The crossover design and the way adverse events were assigned to treatment exposure are not explained in the registry record. The figures do not establish that the groups had equivalent safety profiles, and the event counts do not describe severity beyond the serious-event classification.

Listed serious-event terms include Cellulitis, Corona virus infection, Gastroenteritis viral, Otitis Media, Pneumonia, and Acute renal failure, each reported as 2.0%. The registry record does not report deaths. It does not give further detail in the listed information about event timing, recurrence, attribution, or how multiple events in one participant were handled. These limitations matter when reading descriptive safety counts.

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

The posted result describes a Day 7 pharmacokinetic contrast in stable African-American renal transplant patients. Mean AUC(0-24) was 251.9 ng*hr/mL for Envarsus XR and 247.9 ng*hr/mL for Tacrolimus - IR. The estimated mean difference was -4.0 ng*hr/mL, with a 95% confidence interval from -56.53 to 48.53 and an unadjusted p-value of 0.881. These statistics describe the reported exposure summaries and the uncertainty attached to their contrast.

The result does not show that the true mean difference is zero. The confidence interval includes values on both sides of zero, and its breadth leaves uncertainty about the direction and size of the contrast. Nor does the result demonstrate equivalence: equivalence requires a prespecified margin and an appropriate analysis, and such details are not reported in the registry record. A non-small p-value is not proof that two treatments have identical exposure.

The endpoint is pharmacokinetic, not a clinical outcome. It does not directly report transplant success, graft function, rejection, or long-term safety. The findings should not be generalized beyond the study population and setting without supporting evidence. The record describes a single-center study and does not report the detailed analysis needed to assess how the crossover structure was handled.

Adverse-event counts are descriptive and do not establish that one treatment is safer or less safe. The registry lists serious events affecting 3 participants with Envarsus XR and 4 with Tacrolimus - IR, with 50 at risk in each group. The basis for assigning events to treatments in the crossover setting is not explained.

Overall, the registry result is best read as an imprecise estimate of a Day 7 exposure contrast, not as a definitive claim about equality, clinical benefit, or safety. Further interpretation is constrained by missing analysis details and the absence of posted secondary outcome results.

16. Why This Trial Matters Statistically

This trial is statistically notable because its crossover structure offers the possibility of comparing treatments within participants, while also requiring methods that account for the resulting dependence. That distinction is important: a crossover is not simply a parallel-group study conducted in periods. Sequence and period effects can influence estimates, and valid uncertainty calculations depend on how the repeated measurements are modeled. The registry record identifies the design but does not report those analysis details.

The primary result illustrates why effect estimates and confidence intervals deserve attention alongside p-values. The mean difference is -4.0 ng*hr/mL, but its confidence interval extends from -56.53 to 48.53. The estimate is near zero, yet the interval allows for a range of possible differences. A p-value of 0.881 does not resolve that uncertainty or establish equivalence.

The endpoint also raises an important measurement question. AUC(0-24) summarizes exposure over a dosing interval, using concentrations collected at multiple time points. This is a relevant pharmacokinetic measure when comparing once-daily and twice-daily dosing schedules, but it remains an exposure measure rather than a clinical outcome. Clear separation between pharmacokinetic and clinical conclusions prevents overinterpretation.

Finally, the posted record leaves key analytic questions unanswered, including missing-data handling, multiplicity procedures, and the treatment of crossover effects. Those omissions do not invalidate the reported summary, but they limit independent assessment of its assumptions and precision. The study is a useful example of why trial design, estimand, analysis method, and uncertainty must be read together.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation for statistical interpretation is that the registry record does not report the detailed analysis model for the crossover data. In particular, it does not explain whether within-participant pairing was used or how sequence and period effects were handled. This prevents a full evaluation of the reported standard errors, confidence interval, and p-value in light of the design.

The primary outcome uses a PK population of N=46, while enrollment is 50. The reason for this difference is not reported in the registry record. Missing-data procedures, incomplete profile handling, exclusions, and sensitivity analyses are also not reported. The result may therefore be difficult to assess for potential selection or missingness effects.

The study is described as open label and single-center. The record does not describe any safeguards related to open-label conduct or provide information about generalizability beyond the study population. It identifies a two-sequence, three-period crossover design but does not report sequence details or washout procedures.

The record lists nine outcome measures but posts no secondary outcome results. It does not report a multiplicity strategy, the original sample-size justification, interim analyses, or a detailed statistical analysis plan. The posted result is consequently limited to the stated primary exposure summary and comparison. These limitations are specific to interpretation of the available registry information and should not be taken as evidence that unreported procedures were absent.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Crossover Study to Compare PK of Once Daily LCP-Tacro Tablets to Generic Tacrolimus Capsules Twice Daily. — NCT01962922.
• Registry record last updated 2018-06-06; status last verified 2018-05.
• Results first posted 2016-08-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

The record describes a completed, randomized, open-label, single-center, two-sequence, three-period crossover study comparing once-daily Envarsus XR with twice-daily Tacrolimus - IR in stable African-American renal transplant patients. It is listed as Phase 3, with enrollment of 50 and dates of 2013-11 to 2015-07.

The primary endpoint was Day 7 AUC(0-24) in ng*hr/mL. The PK population was N=46. Mean values were 251.9 for Envarsus XR and 247.9 for Tacrolimus - IR; the mean difference was -4.0, with a 95% confidence interval from -56.53 to 48.53 and unadjusted p-value of 0.881. Secondary outcomes are not posted, and detailed crossover analysis and missing-data methods are not reported in the registry record.