A Study of Effects of Selpercatinib (LY3527723) on Repaglinide in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Effects of Selpercatinib (LY3527723) on Repaglinide in Healthy Participants (NCT05469113), a non-randomized phase 1 study. The primary outcome is Pharmacokinetics (PK): Area Under the Concentration-time Curve, From Time 0 to the Last Observed Non-zero Concentration (AUC0-t) of Repaglinide.

2. Clinical Question

3. Trial Design

This was a phase 1, open-label, non-randomized, sequential study in healthy participants. The registry record describes a fixed sequence: participants received repaglinide alone in Period 1, followed by repeated selpercatinib and then selpercatinib co-administered with repaglinide in Period 2. The study was completed. The recorded enrollment was 16 participants, and the study was described as lasting up to 12 days.

In Period 1, participants received a single 0.5 mg repaglinide tablet on Day 1. In Period 2, they received 160 mg selpercatinib capsules twice daily from Day 1 to Day 9. On Day 10, selpercatinib was given twice daily with a single oral 0.5 mg repaglinide tablet in the morning. The primary endpoint measured repaglinide pharmacokinetics in Period 1 and Period 2, with concentration sampling scheduled at predose and multiple post-dose times through 16 hours in each period.

Because treatment sequence was not randomized and there was no masking, the comparison is not equivalent to a randomized, blinded trial. The record identifies the design as sequential and explicitly cautions that the periods are not a like-for-like control comparison. The registry record does not report a separate randomized control group or the statistical method used to compare the pharmacokinetic observations.

The registry record names additional pharmacokinetic outcomes for selpercatinib, including exposure measures, maximum concentration, time to maximum concentration, and trough concentration. It reports 18 outcome measures but no analyses in the analysis count. Detailed information about protocol deviations, the timing of all assessments beyond the stated sampling schedules, or the handling of observations across periods 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.

Period 1

Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who complied sufficiently with the protocol and displayed an evaluable PK profile for this outcome.

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.

Population: All participants who received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetics (PK): Area Under the Concentration-time Curve, From Time 0 to the Last Observed Non-zero Concentration (AUC0-t) of Repaglinide, measured over Period 1: Day 1 (Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 hours post dose); Period 2: Day 10 (Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 hours post dose).

The primary endpoint was repaglinide AUC0-t, the area under the plasma concentration-time curve from time 0 to the last observed non-zero concentration. In pharmacokinetics, an area under the concentration-time curve represents drug exposure over the measured interval. It incorporates concentration information over time rather than describing concentration at just one sampling point. AUC0-t ends at the last observed non-zero concentration, so it is tied to the observed concentration profile and its sampling window.

The registry record specifies that the endpoint was summarized as a geometric mean, with geometric coefficient of variation as the dispersion measure. A geometric mean is commonly used for positive pharmacokinetic measurements that are analysed on a multiplicative scale and may be right-skewed. The geometric coefficient of variation conveys relative variability on that scale; it is not the same as a standard deviation in the original measurement units. These summaries describe the distribution of exposure measurements, but do not alone establish whether the periods differed statistically or clinically.

AUC is used in pharmacokinetic studies because it captures overall measured exposure, which can change even when the peak concentration does not change in the same way. The concentration-time sampling schedule was specified for both periods, with measurements from predose through 16 hours after dosing. The primary endpoint population was restricted to participants with sufficient protocol compliance and an evaluable pharmacokinetic profile. The endpoint estimates, their uncertainty, and the number of participants contributing to the endpoint are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Pharmacokinetic studies describe how drug concentrations change over time after administration. The registry record identifies several such measures for selpercatinib and a primary measure for repaglinide. These measures answer related but distinct questions: area under the curve describes exposure over a period, maximum concentration describes the observed peak, time to maximum concentration describes when that peak occurs, and trough concentration describes the concentration at the end of a dosing interval.

What does AUC0-t represent?

AUC0-t is the area under the concentration-time curve from time 0 to the last observed non-zero concentration. Conceptually, it summarizes the concentration profile across the observation window. If concentrations are higher for more of that window, the area may be larger; if concentrations are lower, it may be smaller. This is a general explanation of the measure, not a statement about the results in this study. The registry record does not report the observed AUC0-t values.

The endpoint’s sampling schedule includes predose and post-dose measurements through 16 hours in both periods. Sampling time points determine what concentration information is available for describing the curve. AUC0-t is specifically tied to the last observed non-zero concentration, rather than necessarily representing exposure over an unlimited interval. The registry record does not report individual concentration profiles or how any missing or non-zero terminal measurements were handled.

Why use a geometric mean?

The primary endpoint was summarized with a geometric mean and geometric coefficient of variation. In general, a geometric mean is appropriate for positive measurements that are naturally interpreted on a multiplicative scale, such as pharmacokinetic exposure. It is calculated using logarithmic values and then returned to the original scale. This can make a summary less dominated by high values than an arithmetic mean when measurements are right-skewed. The geometric coefficient of variation expresses dispersion relative to the geometric mean; it is not a confidence interval and does not indicate the precision of a treatment contrast.

A group-level geometric mean is descriptive. To estimate a contrast between periods, an analysis would also need to define the comparison and its uncertainty. The record does not state whether the analysis used log-transformed values, a paired approach, a model, or another method. It does not report the numerical contrast or its confidence interval. No method should be inferred from the endpoint summary label alone.

How should a confidence interval be understood?

In general, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the statistical method. A narrower interval indicates greater precision than a wider interval, but interpretation also depends on the endpoint, scale, design, and analysis. A confidence interval is not the range containing every participant’s value. No confidence interval for the primary endpoint is reported in the registry record, so precision cannot be evaluated from the posted outcome description.

What does the sequential design imply?

The design places the repaglinide-only period before the period in which repaglinide was administered with selpercatinib. This fixed order can be useful for examining pharmacokinetics under the specified sequence, but it does not provide the protections of randomized allocation. General considerations for sequential studies include possible period effects and changes over time; whether such factors were assessed or adjusted for is not reported in the registry record. The registry record cautions that the arms are not a like-for-like control comparison. It would therefore be inappropriate to describe this as a randomized comparison.

The endpoint population required sufficient protocol compliance and an evaluable pharmacokinetic profile. That definition indicates that endpoint eligibility depended on compliance and the availability of an interpretable profile. The record does not give the number meeting these criteria, the reasons participants may have been excluded, or the approach used for incomplete profiles. These omissions limit assessment of how representative the analysed observations were of all enrolled participants.

Why can variability matter?

Pharmacokinetic measurements can vary between participants and across observations. In general, greater variability makes an estimated contrast less precise, all else being equal. The geometric coefficient of variation is a descriptive measure of relative variability, while an uncertainty interval around a contrast addresses precision of the estimated effect. The registry record lists the dispersion measure for the primary outcome but does not report its numerical value or an interval for the contrast.

Over-dispersion is a general concern when counts or measurements vary more than a statistical model assumes. An analysis that does not account for the relevant distributional features may understate uncertainty. This trial’s registry record does not describe a count model, over-dispersion assessment, or statistical model for the primary endpoint; it is therefore not possible to say whether those methods were relevant or used.

Overall, the endpoint and design information explains what was intended to be measured, but not how the primary comparison was statistically conducted. The analysis model, contrast definition, uncertainty method, and numerical outcome estimates are not reported in the registry record. The available descriptions should therefore be read as design and endpoint information, not as a substitute for a reported statistical analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary pharmacokinetic outcome for repaglinide and secondary pharmacokinetic outcomes for selpercatinib. Multiple outcomes can create a multiplicity issue: when many hypotheses are tested, the chance of at least one apparently notable finding can increase. General approaches include designating a primary outcome in advance, adjusting inference across a defined family of tests, or treating secondary outcomes as descriptive. Which approach was used in this study is not reported in the registry record.

The record identifies 18 outcome measures and reports no analyses in its analysis count. It does not describe a multiplicity adjustment, a hierarchy for testing outcomes, or whether secondary outcomes were intended to support formal inference. Numerical results and inferential statistics for the primary endpoint are also not reported, so the extent to which multiple comparisons affected interpretation cannot be assessed.

The primary pharmacokinetic population included participants who complied sufficiently with the protocol and had an evaluable profile. The number included, the exclusions, and the handling of incomplete or missing measurements are not reported in the registry record. The record does not specify imputation, sensitivity analyses, or how a profile that was not evaluable would be treated. Missing-data methods matter because the observations available for analysis may differ from those initially planned, and the reasons for missingness can affect interpretation.

The registry record also does not describe interim analyses, a detailed statistical analysis plan, or a sample-size justification. Those items should not be inferred from the phase, enrollment, or endpoint definition. The record’s population description provides a criterion for endpoint inclusion, but not enough information to reconstruct the analysis population or assess the effects of missing data.

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 registry record reports serious adverse events and other adverse events separately for each study period or treatment group. For Period 1: Repaglinide (Day 1), 16 participants were listed at risk for serious events and 0 were reported with a serious event; 16 were listed at risk for other events and 7 were reported with an other event. For Period 2: Selpercatinib (Day 1 to Day 9), the corresponding figures were 16 at risk and 0 with a serious event, and 16 at risk and 7 with an other event. For Period 2: Selpercatinib + Repaglinide (Day 10), 13 were listed at risk for serious events and 0 were reported with a serious event; 13 were listed at risk for other events and 11 were reported with an other event.

No deaths are reported in these groups, and the record lists no serious adverse event terms. The other-event counts should not be read as counts of distinct events, nor do they establish that a study drug caused an event. The figures are period-specific; the denominators differ for the co-administration period. The reason for that difference is not reported in the registry record. These counts describe reported safety events and do not quantify repaglinide pharmacokinetics or establish a comparative safety effect.

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

The study was designed to examine whether repaglinide pharmacokinetics differed when repaglinide was administered after repeated selpercatinib dosing, compared with the earlier repaglinide-only period. The primary measure, AUC0-t, captures exposure across the measured concentration-time profile. The registry record gives the endpoint definition, the geometric summary measure, and the sampling schedule.

However, the record does not report numerical primary endpoint results. It therefore does not show the geometric means, the size or direction of a contrast, or the uncertainty around a contrast. Readers cannot determine from the posted results how much repaglinide exposure changed, or how precisely such a change was estimated. The endpoint description alone is not an outcome finding.

The non-randomized fixed sequence also shapes what the design can establish. The comparison is between an earlier period with repaglinide alone and a later period with repaglinide plus selpercatinib, following repeated selpercatinib administration. The registry record warns that these are not like-for-like control arms. Any period comparison would need to be interpreted in relation to the design and the analysis method, which is not reported.

The listed safety counts show no serious adverse events and no deaths in the reported groups, alongside other adverse events. These counts do not determine whether the treatments caused particular events, and they do not replace the missing primary pharmacokinetic results. The group-specific denominators also differ for the co-administration period, with the reason not reported in the registry record.

Thus, the registry record supports a description of the study’s purpose, sequence, endpoint, and reported safety counts. It does not support a numerical conclusion about the primary pharmacokinetic effect or its precision. It also does not provide enough information to assess the full statistical analysis, missing-data handling, or multiplicity strategy. The findings should not be extended beyond what is actually reported in the record.

13. Why This Trial Matters Statistically

This trial illustrates why a clear endpoint definition is not the same as a reported result. AUC0-t is a defined pharmacokinetic measure, and the registry specifies its summary scale and measurement schedule. But without the observed values and an estimate of the comparison, readers cannot quantify the effect or its precision. Statistical interpretation requires both a well-defined measure and reported data tied to an analysis.

It also illustrates the importance of design when interpreting a treatment contrast. The study used a fixed sequence without randomization or masking. The registry record explicitly cautions that the periods are not a like-for-like control comparison. That caveat matters even when a study is focused on pharmacokinetics: an observed difference across periods cannot be interpreted as if treatment assignment had been randomized.

The endpoint population definition highlights another important issue. Only participants with sufficient protocol compliance and an evaluable pharmacokinetic profile were eligible for the primary outcome population. The record does not report how many met that definition or how missing profiles were handled. Without those details, readers cannot fully assess the relationship between enrollment and the analysed data.

Finally, the registry lists multiple pharmacokinetic outcomes and safety counts, yet does not describe the analysis plan or multiplicity approach. A record can give useful information about the question, endpoint, and treatment sequence while leaving essential inferential details unavailable. This study is a reminder to distinguish the planned measurement and descriptive safety counts from the evidence needed to estimate an effect and its uncertainty.

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.

The main limitation for interpretation is that numerical primary endpoint results are not reported in the registry record. No geometric means, period contrast, uncertainty interval, or p-value is available in the record described for this analysis. Without those results, the magnitude, direction, and precision of any difference in repaglinide AUC0-t cannot be assessed.

The study was non-randomized, open-label, and sequential. The registry record explicitly states that the arms are not a like-for-like control comparison. The fixed order means period and treatment conditions coincide; the record does not report whether potential period effects were considered in the analysis. It also does not identify the statistical model or the exact contrast used.

The primary outcome population was defined by protocol compliance and evaluable pharmacokinetic profiles, but its size and composition are not reported. The number of missing or non-evaluable profiles, reasons for exclusion, and missing-data handling are also not reported in the registry record. These details would be important for understanding which observations contributed to the endpoint.

Although the record identifies secondary pharmacokinetic outcomes and safety groups, it does not describe multiplicity control, an analysis hierarchy, or the statistical plan. Safety counts are reported by group, but the reason the co-administration group has a different at-risk denominator is not reported. The record does not provide event terms for the other adverse events in the registry record. These limitations restrict both the statistical interpretation and the level of detail available about participant flow and safety findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Effects of Selpercatinib (LY3527723) on Repaglinide in Healthy Participants — NCT05469113.
• Registry record last updated 2025-12-11; status last verified 2025-11.
• Results first posted 2025-12-11.
• 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

NCT05469113 is a completed phase 1, open-label, non-randomized, fixed-sequence study sponsored by Eli Lilly and Company. It enrolled 16 healthy participants and examined selpercatinib’s effect on repaglinide pharmacokinetics. The record lists a start date of 2019-01-29 and a primary completion date of 2019-03-05.

Participants received 0.5 mg repaglinide alone in Period 1, then repeated 160 mg selpercatinib twice daily followed by co-administration with 0.5 mg repaglinide in Period 2. The primary outcome was repaglinide AUC0-t, summarized using a geometric mean and geometric coefficient of variation. Numerical primary endpoint results and the statistical analysis details are not reported in the registry record.

The safety record lists no serious adverse events and no deaths in the reported groups. Other adverse events were reported by group. The record also lists secondary selpercatinib pharmacokinetic outcomes, but does not report an analysis count above zero.