This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients (NCT01288521), a randomized phase 4 study. The primary outcome is Tacrolimus Bioavailability (F).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01288521 |
| Phase | Phase 4 |
| Condition | Kidney Transplantation |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 8 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Sony Tuteja |
| Results posted | Yes |
2. Clinical Question
Population
The study concerns stable kidney transplant recipients. The primary outcome describes the population as stable kidney transplant recipients, while the brief summary specifies recipients with the CYP3A5 *3/*3 genotype and discusses grouping by ABCB1 haplotype. The registry reports enrollment of 8. Its brief summary describes a plan to enroll 20, so the planned enrollment and the recorded enrollment differ. The registry does not report how many participants belonged to each haplotype group or provide further characteristics of the enrolled population.
Intervention
The intervention condition was tacrolimus given with ketoconazole. The study assessed tacrolimus pharmacokinetics under this coadministration condition, with bioavailability as the primary outcome. The record describes a crossover, with participants receiving both conditions in different sequences.
Comparator
The comparator was tacrolimus alone. In the described sequences, participants received tacrolimus alone either before or after the combination condition, with a washout between periods. The arm descriptions specify a 1-2 week washout; the brief summary describes the assessments as separated by 1 week.
Primary question
The primary question was whether tacrolimus bioavailability differed between treatment conditions: tacrolimus alone and tacrolimus with ketoconazole. The brief summary also frames the study around whether ABCB1 haplotypes can predict the degree of this drug interaction among CYP3A5 nonexpressors. The posted primary outcome reports condition-specific means, and the reported analysis gives a regression p-value. The registry does not report a numerical estimated contrast, confidence interval, or haplotype-specific result, so the posted information does not quantify the size or precision of the condition difference or show whether it varied by haplotype.
3. Trial Design
The registry describes a Phase 4, randomized, open-label crossover study, with enrollment of 8 and status listed as completed. The study start is recorded as 2008-10 and primary completion as 2011-06. Its stated condition is kidney transplantation. The brief summary describes a pharmacokinetic and pharmacogenomic study of tacrolimus in stable renal transplant recipients, with an interest in whether ABCB1 haplotypes predict the interaction between tacrolimus and ketoconazole among CYP3A5 nonexpressors.
In a crossover design, a participant receives more than one treatment condition in separate periods. The listed sequences were tacrolimus with ketoconazole followed by tacrolimus alone, or tacrolimus alone followed by the combination. The arm descriptions state that a 1-2 week washout followed the first period. The brief summary separately describes the two pharmacokinetic assessments as separated by 1 week. These descriptions are both part of the registry record; it does not clarify their relationship.
Random allocation to sequence can help balance order effects, while the crossover permits comparison of conditions within participants. These are general features of the design, not evidence that a particular adjustment or carryover assessment was performed. The record does not report the allocation procedure, sequence-specific participant counts, masking procedures beyond none, or the statistical handling of period or sequence effects.
The brief summary describes an intended enrollment of 20, whereas the registry enrollment field records 8. The registry does not explain the difference. It also does not report a sample-size justification or details of recruitment and completion by sequence. These omissions limit assessment of how the completed study relates to its initial plan.
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: Assignment to the treatment group was based on CYP3A5 genotype and subjects were eligible only if they had the \*3/\*3 genotype. 22 subjects were consented to participate. Based on genotype, 3 subjects were ineligible to complete the study. Of the 19 eligible subjects, 11 declined to participate. 8 subjects completed the study.
Overall Study
| Stage | Tacrolimus + Ketoconazole, Then Tacrolimus Alone | Tacrolimus Alone, Then Tacrolimus + Ketoconazole |
|---|---|---|
| STARTED | 3 | 5 |
| COMPLETED | 3 | 5 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Stable kidney transplant recipients
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.
| Characteristic | Unit | Tacrolimus + Ketoconazole, Then Tacrolimus Alone | Tacrolimus Alone, Then Tacrolimus + Ketoconazole | Total |
|---|---|---|---|---|
| Participants analysed | 3 | 5 | 8 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 2 | 5 | 7 |
| Age, Categorical: >=65 years | Participants | 1 | 0 | 1 |
| Age, Continuous | years | 53 (SD 12.5) | 57 (SD 5.5) | 55.6 (SD 8.2) |
| Sex: Female, Male: Female | Participants | 1 | 1 | 2 |
| Sex: Female, Male: Male | Participants | 2 | 4 | 6 |
| Region of Enrollment: United States | participants | 3 | 5 | 8 |
6. Primary Endpoint
The registry lists the primary outcome as Tacrolimus Bioavailability (F), measured over baseline and 2 weeks.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | ratio of oral to IV |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is tacrolimus bioavailability, denoted F, with the unit described as a ratio of oral to IV. The registry description says F was calculated as the area under the curve after an oral dose divided by the area under the curve after an IV dose. It also says F was determined by fitting a model that considered plasma tacrolimus concentration with IV versus oral dosing. The endpoint is assessed for tacrolimus alone and tacrolimus with ketoconazole, at baseline and 2 weeks.
Bioavailability is a pharmacokinetic measure of the extent to which a drug reaches systemic circulation after administration. In general, comparing oral and IV exposure can help characterize the fraction of an oral dose that becomes available, since IV administration enters the circulation directly. This is a general explanation of the measure, not an additional result from the study.
The registry reports the endpoint as a continuous measure summarized by its mean and standard deviation. A continuous outcome can retain differences in magnitude rather than reducing observations to categories. The posted values describe the two treatment conditions, but the record does not give a confidence interval for their contrast or a numerical contrast estimate. It also does not provide participant-level exposure values or a fuller description of the fitted model.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry reports mean tacrolimus bioavailability of 0.224 with tacrolimus alone and 0.681 with tacrolimus plus ketoconazole. The corresponding standard deviations are 0.107 and 0.308. These are descriptive summaries for the two conditions, not a reported estimate of the paired treatment contrast. Because the design is crossover, the most direct comparison would generally use within-participant information; the posted group summaries do not reveal the individual paired differences.
The reported analysis is described as linear regression, and its p-value is 0.006. A p-value describes how compatible the observed data are with a specified null model under the analysis assumptions; it does not measure the size of an effect, its clinical importance, or the probability that the null hypothesis is true. The registry does not report the regression coefficient, confidence interval, model specification, or exact null hypothesis. Therefore the p-value cannot by itself show the magnitude or precision of the contrast, nor establish which model terms were included.
The means are numerically different, but a difference calculated from the two displayed means would not be the same as a participant-level crossover estimate. No such recalculated contrast is available in the registry record: the record marks a two-arm continuous comparison as missing or not estimable for recalculation. The reported analysis therefore remains the available inferential result. The registry does not flag a discrepancy between its analysis and a recalculation.
Precision is especially important when interpreting a small study. The reported standard deviations describe variation in each condition, but they are not confidence intervals and do not directly describe the precision of the paired contrast. A confidence interval for a treatment contrast would show a range of values compatible with the data and model, incorporating uncertainty in the estimate. No such interval is reported.
The record provides no haplotype-stratified outcome estimates, despite the brief summary's interest in ABCB1 haplotypes. Consequently, the posted outcome does not establish whether the condition contrast differed by haplotype. Nor does the registry provide secondary outcomes. The numerical summaries and p-value should be read as evidence about this registered pharmacokinetic comparison, with substantial limits on what can be inferred about its size, precision, subgroup pattern, or broader applicability.
9. Statistical Methods Explained
What does the reported p-value tell the reader?
The registry reports a p-value of 0.006 for an analysis described as linear regression. In general, a p-value measures how unusual data at least as incompatible with a specified null model would be, if that model and the analysis assumptions were correct. It is not the probability that the null hypothesis is true, and it does not quantify the effect size. A small p-value can accompany an imprecisely estimated effect, particularly when the estimate itself and its uncertainty are not reported.
The registry does not state the null hypothesis in detail, provide a regression coefficient, identify the model terms, or give a confidence interval. It is therefore not possible from the record to determine precisely what contrast the regression tested or how it accounted for the crossover structure. The p-value is the inferential result that is posted, but it should not be interpreted as a full report of the model or its estimate.
Why do the group summaries not reproduce the crossover comparison?
The posted means and standard deviations summarize tacrolimus bioavailability separately for the two conditions. A crossover comparison ordinarily benefits from knowing how each participant's measurements change between conditions. The pairing of the measurements affects the uncertainty of a within-participant contrast. Marginal means and standard deviations alone do not reveal that pairing or the covariance between measurements.
For this reason, a contrast reconstructed only from the two condition summaries would not necessarily match a paired or regression-based estimate. The registry record marks recalculation of a two-arm continuous comparison as missing or not estimable. No recalculated contrast or confidence interval is available to compare with the reported regression result. The registry does not flag a discrepancy, but the absence of a recalculation is not proof that every analytical detail can be independently verified.
What do standard deviations and confidence intervals represent?
In general, a standard deviation describes the spread of observations around a group mean. It does not show the precision of the mean or of a treatment contrast by itself. A confidence interval describes uncertainty in an estimated quantity under a statistical model and its assumptions. For a crossover treatment contrast, the interval would ideally reflect the paired design and the analysis used.
The record reports standard deviations of 0.107 for tacrolimus alone and 0.308 for tacrolimus with ketoconazole. It does not report confidence limits for the means or for their contrast. Thus the posted summaries show variation within each condition, but they do not provide a direct measure of uncertainty for the treatment comparison.
Why does the crossover structure matter?
In general, crossover designs compare conditions within participants, potentially controlling for stable participant characteristics. The sequence and period in which a condition is received can matter. A washout is intended to separate treatment periods, but the registry's description alone does not demonstrate that carryover was absent. The record says the study was unmasked and randomized, but does not report a period-effect analysis, sequence-effect analysis, carryover assessment, or model details. Those procedures should not be assumed.
The brief summary describes pharmacokinetic assessments on two occasions with and without ketoconazole separated by 1 week. The arm descriptions state a 1-2 week washout. The record does not explain the difference in wording. It also does not provide the allocation details or the number of participants in each treatment sequence.
What can sample-size planning illustrations say?
General sample-size calculations can illustrate how many participants per arm might be needed to detect a chosen fraction of an observed effect under stated assumptions. Such illustrations depend on assumptions about the effect, variability, allocation, significance level, and analysis. They are planning aids, not evidence about the study's actual power or what would happen in another study. The registry's planning description specifies a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. It distinguishes participants per arm for ordinary outcomes from total events for time-to-event outcomes.
No actual illustration values or fractions are included in the record, so no specific planning requirement can be stated. These calculations are not observed power. The trial's own sample-size justification and its assumptions are not reported in the registry record. The enrollment recorded as 8 should not be confused with a calculated sample-size target.
What is not documented about the analysis?
The registry provides one primary outcome, one reported analysis, and no posted secondary outcomes. It does not report a detailed statistical analysis plan, analysis population, missing-data handling, model diagnostics, or adjustment for period, sequence, or haplotype. General statistical considerations can identify why these details matter, but their use in this study cannot be inferred. The results should therefore be read at the level of detail actually documented: condition-specific descriptive statistics and a regression p-value, without a posted estimate and interval for the contrast.
10. Confidence Intervals for Each Arm
No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.
| Arm | Participants | Mean | Standard deviation | 95% CI for the mean |
|---|---|---|---|---|
| Tacrolimus Alone | 8 | 0.224 | 0.107 | 0.135 to 0.313 |
| Tacrolimus + Ketoconazole | 8 | 0.681 | 0.308 | 0.424 to 0.938 |
R code and output
arm <- c("Tacrolimus Alone", "Tacrolimus + Ketoconazole")
n <- c(8, 8)
m <- c(0.224, 0.681)
sp <- c(0.107, 0.308)
sd <- sp # posted standard deviations
for (i in seq_along(n)) {
se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}
CARM Tacrolimus Alone 8 0.224 0.107 0.135 0.313
CARM Tacrolimus + Ketoconazole 8 0.681 0.308 0.424 0.93811. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Regression, Linear | not reported | 0.006 |
The registry's own analysis is described as linear regression and reports p = 0.006. It does not report a regression coefficient, confidence interval, or enough model detail to reconstruct the analysis from the posted summary statistics. The record also indicates that recalculation of a two-arm continuous comparison is missing or not estimable. As a result, there is no independent recalculated effect estimate or interval to compare directly with the sponsor's result.
The record does not flag a discrepancy between the posted analysis and a recalculation. That absence should not be mistaken for a validation of the regression model: the necessary model specification and paired data are not reported. The sponsor's analysis is therefore the available inferential result, while its effect size and precision remain unquantified in the registry record.
In general, an analysis based on participant-level crossover data may use information not recoverable from separate condition means and standard deviations. The registry does not say whether the regression accounted for within-participant pairing, treatment sequence, period, or other factors. The p-value should be reported as stated, without assigning it a more specific interpretation than the record supports.
12. Multiplicity, Missing Data and Analysis Populations
The registry identifies one primary outcome, tacrolimus bioavailability, and one reported analysis. It lists no secondary posted outcomes. The record does not describe a multiplicity strategy, such as a prespecified hierarchy, an adjustment across multiple tests, or a decision to treat a single comparison as the sole confirmatory analysis. With no such information, it is not possible to determine whether the reported p-value was adjusted for other analyses or whether additional analyses were conducted but not posted.
Multiplicity is a general concern when many outcomes, subgroups, time points, or models are tested: the chance of at least one apparently notable result can increase as the number of tests grows. The brief summary's scientific question includes ABCB1 haplotypes, but the registry does not post haplotype-specific results or explain whether subgroup analyses were planned. This does not establish that such analyses were conducted; their status is not reported in the registry record.
The record does not describe missing-data handling, exclusions, or the analysis population used for the regression. It reports enrollment of 8 and condition-specific group summaries with n = 8. Those summaries do not establish whether all randomized participants completed both periods or whether every enrolled participant contributed to the model. The registry also does not provide participant flow by sequence or period.
In a crossover study, missing measurements in either period can affect which participants contribute to a paired comparison. General approaches may include analysis of complete pairs or model-based methods, but the registry does not identify the approach used. Nor does it report a sensitivity analysis for missing outcomes. These omissions make it difficult to assess whether missingness could have influenced the reported comparison. The absence of details should be understood as incomplete reporting, not as evidence that missing data occurred or did not occur.
13. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Tacrolimus Alone | 0 | 8 | 0.0% |
| Tacrolimus + Ketoconazole | 0 | 8 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Tacrolimus Alone | 0 of 8 |
| Tacrolimus + Ketoconazole | 0 of 8 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Tacrolimus Alone | 0 of 8 |
| Tacrolimus + Ketoconazole | 0 of 8 |
The registry reports zero serious adverse events and zero deaths in both treatment conditions. It also reports zero other adverse events in both conditions. The at-risk count is 8 for each condition in the serious-event and other-event summaries. No serious adverse event terms are listed.
These are the adverse-event figures posted for this study. A zero count means no events of the listed type were recorded in the registry outcome summary; it does not establish that an event is impossible or that a treatment is free of risk. In general, safety estimates from a small study have limited ability to characterize uncommon events. The registry does not provide event definitions, collection procedures, severity details, causal assessments, or a narrative account of safety monitoring.
The crossover structure also means the same participants may contribute to both treatment conditions. The condition-specific counts should not be interpreted as counts from separate participant groups. The record does not report the timing of events by period or provide additional detail about exposure during each condition. These figures are descriptive registry results and do not support broader safety conclusions.
14. What the Result Does, and Does Not, Mean
The posted results show that mean tacrolimus bioavailability was 0.224 with tacrolimus alone and 0.681 with tacrolimus plus ketoconazole. The reported standard deviations were 0.107 and 0.308, respectively. A linear regression analysis is reported with p = 0.006. These results describe the registered pharmacokinetic comparison in this study; the record does not supply a numerical adjusted or paired contrast, confidence interval, or full model description.
The result does not, by itself, show the magnitude or precision of the within-participant difference. Nor does it establish how the association varies across ABCB1 haplotypes: no haplotype-specific outcome estimates are posted. The registry describes this as a study of stable kidney transplant recipients and its brief summary focuses on a particular genotype, but the posted results do not document enough detail to assess subgroup composition or applicability to other populations.
A p-value is not a measure of clinical importance, and the study's pharmacokinetic endpoint is not a direct report of clinical outcomes. The record does not report outcomes such as rejection, graft function, or long-term consequences as primary or secondary results. No treatment recommendation follows from this statistical summary.
The enrollment recorded as 8 is limited for characterizing variability or uncommon outcomes. The brief summary describes an intended enrollment of 20, but the record does not explain the difference. The reported adverse-event counts are zero in the listed categories, but they do not prove absence of risk. Overall, the registry supports a description of condition-specific bioavailability summaries and a reported regression p-value, while leaving important questions about the estimated contrast, uncertainty, analysis details, and subgroup pattern unresolved.
15. Why This Trial Matters Statistically
This study illustrates several statistical issues that arise in pharmacokinetic crossover research. The same participant can receive both treatment conditions, so the comparison can use within-participant information. That structure can be valuable, but a reader needs the pairing information or a sufficiently detailed model report to interpret the estimated contrast and its uncertainty. Separate means and standard deviations cannot reveal the pattern of individual changes.
The registry provides condition-specific summaries and a regression p-value, but not the regression estimate or confidence interval. This distinction matters: evidence against a null model is not a substitute for quantifying the size and precision of the contrast. The record also describes a pharmacogenetic question about ABCB1 haplotypes without reporting haplotype-specific estimates. A broad study question and an available overall comparison are not interchangeable evidence about subgroup differences.
The different enrollment descriptions also matter for transparent reporting. The registry enrollment field records 8, while the brief summary describes a plan to enroll 20. The record does not explain the difference. Careful interpretation separates the stated plan from the recorded enrollment rather than assuming why they differ.
Finally, zero adverse-event counts need cautious interpretation, particularly when the recorded enrollment is small. The figures describe what was posted, not a guarantee about risk. Taken together, the study is a useful example of how design, estimand, reporting completeness, and precision shape the conclusions readers can draw from a p-value and descriptive summaries.
16. 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 registry record leaves key aspects of the primary comparison unreported. Although it gives the condition means, standard deviations, and a regression p-value, it does not provide the regression coefficient, confidence interval, model specification, or a precise statement of the contrast tested. The recalculated two-arm continuous comparison is marked missing or not estimable. Consequently, the effect size and its precision cannot be independently assessed from the posted summaries.
The study is described as a crossover, but the record does not state how the analysis accounted for within-participant pairing, treatment sequence, period, or possible carryover. The brief summary describes assessments separated by 1 week, while the arm descriptions state a 1-2 week washout; the registry does not reconcile these descriptions. Allocation details beyond randomized assignment are not reported.
The stated scientific interest includes ABCB1 haplotypes, yet no haplotype-specific results are posted. The record does not provide subgroup sizes, participant characteristics beyond the stated population, or a detailed analysis population. It also does not describe missing-data procedures, participant flow, model diagnostics, or sensitivity analyses. The intended enrollment of 20 in the brief summary differs from the enrollment field of 8, with no explanation.
Safety reporting is limited to event counts and at-risk counts. Event definitions, timing, severity, and attribution are not reported. There are no secondary posted outcomes to broaden interpretation. These limitations concern the completeness and precision of the registry record; they do not establish that unreported procedures or results were absent from the conduct of the study.
17. Related Tutorials
18. Related Statistical Calculators
19. Sources
- ClinicalTrials.gov: Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients — NCT01288521.
- Registry record last updated 2018-03-09; status last verified 2018-02.
- Results first posted 2018-03-09.
- 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.
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Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
20. Record Summary
The registry describes a completed, randomized, open-label, Phase 4 crossover study of tacrolimus alone versus tacrolimus with ketoconazole in stable kidney transplant recipients. Enrollment is recorded as 8. The brief summary describes an intended enrollment of 20 and a pharmacogenetic question involving ABCB1 haplotypes among CYP3A5 nonexpressors.
The primary outcome is tacrolimus bioavailability, expressed as a ratio of oral to IV exposure. The posted mean was 0.224 with tacrolimus alone and 0.681 with the combination; the reported standard deviations were 0.107 and 0.308. The registry reports a linear regression p-value of 0.006 but no estimate or confidence interval for the contrast. The record reports zero serious adverse events, zero other adverse events, and zero deaths in each condition. Interpretation is limited by the missing model details, uncertainty interval, and haplotype-specific results.