Study of the Effects of Itraconazole and Rifampin on LOXO-305 in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Effects of Itraconazole and Rifampin on LOXO-305 in Healthy Participants (NCT05134337), a non-randomized phase 1 study. The primary outcome is Part 1: Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of LOXO-305.

2. Clinical Question

The broader study title also identifies a Part 2 investigation involving rifampin. In that part, LOXO-305 was administered alone and on specified days with rifampin. The registry record therefore describes two drug-interaction questions within a single study, rather than a randomized comparison of treatments. Its focus is drug concentration in plasma, not a clinical benefit or disease outcome. The registry record does not report results that establish the size or direction of either interaction.

3. Trial Design

This was a Phase 1, open-label, non-randomized, sequential study with two parts. It enrolled 27 healthy participants and is listed as completed. The registry identifies no masking. These design features matter when interpreting the comparisons: treatment order was fixed rather than randomized, and participants and study personnel were not masked to treatment.

Part 1 examined LOXO-305 with itraconazole. Participants received a single oral dose of 200 mg LOXO-305 on Day 1. Itraconazole was administered on Day 8 as 200 mg twice daily, followed by 200 mg once daily on Days 9 to 18. The description says that itraconazole was co-administered with LOXO-305 on Day 12, but the remainder of that dosing detail is not reported in the registry record.

Part 2 examined LOXO-305 with rifampin. Participants received a single oral dose of 200 mg LOXO-305 on Day 1. Rifampin was administered as 600 mg once daily on Days 8 to 23, and was co-administered with a single oral dose of 200 mg LOXO-305 on Days 8 and 17.

The study structure permits pharmacokinetic observations under specified dosing conditions, but it does not provide randomized parallel treatment groups. The registry record does not report a protocol-level rationale for the sequence, a sample-size justification, or details sufficient to reconstruct all aspects of the dosing and analysis procedures. The study's planned participation duration was described as about 8 weeks.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All part 1 participants who received a dose of LOXO-305 on day 1, itraconazole with LOXO-305 on day 12, had at least one quantifiable plasma concentration of LOXO-305, and had at least one PK parameter computed for the specified timepoints. Participants were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median time to maximum observed plasma concentration (Tmax).

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 enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of LOXO-305, measured over Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose on days 1 and 12.

The primary endpoint is the maximum observed plasma concentration, or Cmax, of LOXO-305 in Part 1. Cmax is the highest measured concentration in the scheduled blood-sampling profile after dosing. It describes the peak concentration observed during that profile; it does not by itself describe the full concentration-time curve, total exposure, duration of exposure, or a clinical outcome.

The registry specifies Cmax in nanograms per milliliter and identifies the reported summary as a geometric mean with geometric coefficient of variation. A geometric mean is a summary suited to positive measurements that may be right-skewed. The geometric coefficient of variation describes relative variability on a multiplicative scale; it is not the same as a confidence interval and does not directly show uncertainty in a treatment comparison.

For the primary measure, the registry lists sampling from predose through 168 hours postdose on days 1 and 12. These repeated measurements are used to identify the observed peak for the specified dosing conditions. The primary endpoint's numerical estimates and any comparison between conditions are not reported in the registry record. The endpoint definition alone therefore does not reveal whether concentrations differed, by how much, or with what precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a pharmacokinetic endpoint summarized by a geometric mean and geometric coefficient of variation. It does not report a detailed statistical analysis plan, the primary numerical estimates, or inferential results. The general explanations below clarify what these statistical terms mean, not what the study found.

What does Cmax represent?

In general, a concentration-time profile records measured drug concentrations at scheduled times after administration. Cmax is the greatest observed concentration in that profile. It is a peak measure, and its value depends in part on the sampling schedule: a peak between scheduled samples may not be directly observed. The listed Part 1 schedule includes predose and multiple postdose time points through 168 hours on days 1 and 12. The registry gives the schedule but does not report individual concentration profiles or Cmax values.

Cmax is one way to characterize pharmacokinetics. It should not be treated as a complete description of exposure. Other characteristics, such as overall exposure or the time at which the peak occurs, are distinct measures. The registry names seven outcome measures in total, but the full set of outcome results is not reported in the registry record described for this analysis.

Why use a geometric mean?

General: drug concentration measurements are positive and can have a distribution in which a small number of high values extend the upper tail. A geometric mean summarizes positive values on a multiplicative scale and can be more suitable than an arithmetic mean for such data. It is commonly interpreted through ratios rather than additive differences. This explanation does not establish which summary or comparison was used for the study's treatment effect; that detail is not reported in the registry record.

The geometric coefficient of variation expresses variability relative to the geometric mean on a multiplicative scale. It is a descriptive measure of spread among observations, not a confidence interval around a comparison. A coefficient of variation alone does not establish how precisely a treatment effect is estimated. The numerical geometric means and variability estimates for the primary endpoint are not reported in the registry record.

What would a confidence interval add?

General: a confidence interval gives a range of values compatible with an estimate under the statistical model and sampling assumptions used. It conveys uncertainty about the estimated effect, whereas a point estimate alone gives only its central value. Interpreting such an interval would require knowing the estimate, interval limits, and analysis method. The registry record does not report a confidence interval for the primary Cmax comparison.

A statistical test and its p-value address a different question from the size and precision of an effect. A p-value is not a measure of clinical importance, and a result that crosses a chosen threshold does not replace examination of the estimated effect and its uncertainty. No p-value for the primary Cmax comparison is reported in the registry record.

How does the sequence affect interpretation?

General: a fixed-sequence design administers conditions in a prescribed order rather than assigning participants randomly to concurrent groups. This allows measurement under different planned dosing conditions, but it does not have the same protection against systematic differences between groups that randomization provides. Time, order, and other changes across the sequence can complicate interpretation. The registry record does not report a detailed model or adjustments for such issues.

The study is open label and non-randomized. These design labels do not invalidate pharmacokinetic measurement, but they describe features relevant to interpretation. The registry record does not report masking procedures, a randomization scheme, or a detailed statistical model. It also does not report whether or how the analysis accounted for within-participant dependence across conditions.

How should planning calculations be understood?

General: a sample-size calculation describes the number of participants or events that a hypothetical study would need under specified assumptions. The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They also define the effect to detect as a stated fraction of the observed effect. These are planning assumptions, not evidence about the study's actual treatment effect.

Such illustrations are not observed power. Observed power is not an appropriate substitute for reporting the estimated effect and its uncertainty. The registry record does not report the numerical observed effect or the planning illustration outputs in the registry record, so no numerical sample-size implication can be interpreted. More broadly, the detailed analysis procedures, including any model used for the pharmacokinetic data, are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures but reports zero analyses. The primary outcome is identified as Part 1 Cmax of LOXO-305. The record does not provide a statistical analysis plan describing how that endpoint relates to the other outcome measures, which outcome was designated for formal testing, or whether any adjustment for multiple testing was planned.

Multiplicity can arise when several endpoints, comparisons, or analysis choices are examined. In general, testing many hypotheses without an appropriate plan can increase the chance of finding an apparently notable result by chance. This general concern does not establish that multiplicity affected this study. The registry record does not report a multiplicity procedure or enough analysis results to assess its application.

The primary population description specifies participants who received LOXO-305 on Day 1 and with itraconazole on Day 12, had at least one quantifiable LOXO-305 plasma concentration, and had at least one pharmacokinetic parameter computed for the specified timepoints. The description ends before all exclusion criteria are given. The complete analysis-population definition and the number of participants included are not reported in the registry record.

Missing-data procedures are also not reported in the registry record. The record does not explain how missing concentration measurements, incomplete profiles, or participants with no computable pharmacokinetic parameter were handled. It does not report whether missingness was assessed or whether any sensitivity analyses were conducted. Without those details and the numerical outcome results, the potential influence of incomplete data cannot be evaluated.

The reported enrollment count and the counts in the adverse-event groups do not, by themselves, establish how many participants contributed to each pharmacokinetic analysis. The record does not report a complete participant flow for the primary endpoint or explain all differences between the listed safety groups.

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 non-serious adverse event terms

The registry reports no serious adverse events and no deaths in any of the listed groups. For Part 1, the groups are 200 mg LOXO-305 alone, 200 mg itraconazole alone, and 200 mg LOXO-305 with 200 mg itraconazole. The numbers at risk are 15, 12, and 12, respectively, and the number affected by serious events is 0 in each group.

For Part 2, the groups are 200 mg LOXO-305 alone, 200 mg LOXO-305 on Day 8 with 600 mg rifampin, and 200 mg LOXO-305 on Day 17 with 600 mg rifampin. Each has 12 participants at risk; serious events and deaths are 0 in each group.

The registry separately records other adverse events. It reports 2 participants affected in the Part 1 itraconazole-alone group, 1 in the Part 1 combination group, and 1 in the Part 2 Day 17 combination group. The other listed groups report 0 participants affected. These counts are not serious-event counts.

These are descriptive counts in a small healthy-participant study, not a randomized safety comparison. The registry does not provide the event terms or further details for the affected participants in the registry record described. A zero count means no events of that category were recorded in that group; it does not establish that an event is impossible or characterize safety in other populations.

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

The study record documents a Phase 1 investigation of the pharmacokinetics of LOXO-305 under conditions involving itraconazole and rifampin in healthy participants. It gives dosing schedules and defines a primary Part 1 measure, Cmax. Those details explain what the study was designed to examine, but they do not supply the numerical result needed to quantify an interaction.

Because the primary Cmax estimates and comparison are not reported in the registry record, the direction and magnitude of the Part 1 result cannot be stated. The record also does not report numerical pharmacokinetic findings for Part 2. It therefore does not support a quantitative conclusion about the effect of either coadministered drug on LOXO-305 concentration.

The design is sequential and non-randomized, rather than a randomized comparison of parallel arms. Its treatment conditions were administered in a fixed sequence, and the study was open label. These features should inform interpretation of any reported comparison. They do not, on their own, determine what the pharmacokinetic result would be.

The record concerns healthy participants and reports no clinical disease outcome. Cmax is a concentration measure, not a direct measure of clinical benefit. No medical conclusion about treatment effectiveness follows from the endpoint description or the safety counts. The record reports zero serious adverse events and zero deaths in each listed group, alongside a small number of participants affected by other adverse events in some groups. Those observations are descriptive and should not be generalized beyond the study population and recorded groups.

The distinction between an endpoint definition and an endpoint result is central. A sampling schedule and a summary statistic describe how an outcome can be measured; they do not reveal its estimate, variability, or uncertainty. Without the primary numerical result and its statistical uncertainty, the registry record does not permit assessment of how precisely an interaction was estimated.

13. Why This Trial Matters Statistically

This study illustrates why pharmacokinetic interaction questions require more than a dosing description. The registry specifies the compounds, the sequence of administration, and the primary concentration measure. These features help define the scientific question and the conditions under which concentrations were intended to be assessed. But without posted estimates and measures of uncertainty, the central quantitative finding cannot be interpreted.

It also highlights the importance of distinguishing peak concentration from other aspects of pharmacokinetics. Cmax captures the maximum observed concentration in a sampling profile. It does not alone describe the full time course or overall exposure. The geometric mean and geometric coefficient of variation provide a particular way to summarize concentration data and their relative variability, but they are not substitutes for a treatment-effect estimate and its confidence interval.

The fixed-sequence, non-randomized design is statistically relevant. Comparisons across sequential conditions do not have the same structure as comparisons between concurrent randomized groups. A clear analysis should explain how the ordered conditions and participant-level measurements were handled. Those analytic details are not reported in the registry record.

Finally, the record illustrates the difference between statistical planning and observed evidence. Planning calculations rely on assumptions about an effect and a target design; they are not results and do not represent observed power. The registry describes assumptions for planning illustrations, but the numerical outcome needed to interpret an observed effect is not reported. Taken together, the design and endpoint information clarify the intended investigation while leaving its quantitative pharmacokinetic findings unresolved in the registry record.

14. Limitations

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

A key limitation for interpreting the posted information is that no numerical primary Cmax result is reported in the registry record. The record also does not report a confidence interval, p-value, or numerical comparison for the itraconazole condition. Numerical pharmacokinetic results for the rifampin part are likewise not reported. As a result, neither the size nor the precision of the drug-interaction findings can be assessed from this record.

The study was non-randomized, open label, and sequential. It therefore does not provide a randomized, masked comparison between parallel treatment groups. The registry record does not report detailed methods for separating treatment-condition effects from possible sequence or time effects, or whether within-participant correlation was incorporated in the analysis.

The primary analysis-population description is incomplete: it states eligibility criteria based on dosing and quantifiable concentration data, then ends before all exclusion details are given. The number included in the primary analysis and the handling of missing or incomplete pharmacokinetic profiles are not reported in the registry record. The record also does not report a detailed statistical analysis plan or a multiplicity strategy for the seven outcome measures.

The study enrolled healthy participants, so its population is limited to that setting. The safety information is presented as counts across specified groups, but detailed event terms are not reported in the registry record described. The registry record does not provide enough information to evaluate event timing, duration, or severity beyond its serious-event classification. These limitations concern what can be concluded from the registry record and do not establish that additional study information does not exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of the Effects of Itraconazole and Rifampin on LOXO-305 in Healthy Participants — NCT05134337.
• Registry record last updated 2025-01-09; status last verified 2024-11.
• Results first posted 2025-01-09.
• 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.

18. Record Summary

NCT05134337 is a completed Phase 1, open-label, non-randomized, sequential study enrolling 27 healthy participants. It investigated LOXO-305 with itraconazole in Part 1 and with rifampin in Part 2. The primary outcome is Part 1 maximum observed plasma concentration of LOXO-305, summarized as a geometric mean with geometric coefficient of variation. The registry record describes dosing schedules and sampling times but does not report the primary numerical result or a statistical comparison. It lists zero serious adverse events and zero deaths in each adverse-event group, and reports some other adverse events in three groups. Detailed statistical methods, complete analysis-population information, and missing-data procedures are not reported in the registry record.