A Study to Evaluate the Effect of Pirtobrutinib (LOXO-305) on QTc Interval in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Effect of Pirtobrutinib (LOXO-305) on QTc Interval in Healthy Participants (NCT06215521), a randomized phase 1 study. The primary outcome is Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF).

2. Clinical Question

3. Trial Design

This was a Phase I, randomized, partially double-blind, placebo- and positive-controlled, 3-way crossover study in healthy participants. The registry lists enrollment as 31 and study status as completed. The recorded start date was 2020-12-15, and the primary completion date was 2021-03-31. The study was sponsored by Eli Lilly and Company.

The three treatments were pirtobrutinib, matched placebo and moxifloxacin. Each arm description specifies a single oral dose on Day 1, 12 and 23, with fasting for at least 8 hours before and 6 hours after dosing. The safety group titles identify 900 mg pirtobrutinib and 400 mg moxifloxacin. The registry summary says the study could last up to 71 days, including screening.

In a crossover design, treatment comparisons can use measurements collected from the same participant under different treatment conditions. This can help account for stable differences between participants. It also makes the treatment sequence, period effects, carryover and completeness of measurements relevant to interpretation. The registry record does not report the treatment sequences, period-specific results, washout details or the methods used to assess period or carryover effects. Randomization and partial double blinding are stated, but further operational details about allocation and masking are not reported in the registry record.

The study also assessed blood concentrations and how the body handles and eliminates pirtobrutinib, as well as safety and tolerability. Those aims are described in the registry summary; detailed results for them 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.

Before assignment: A total of 31 participants were enrolled in this study. Participants were randomly assigned to 1 of 6 treatment sequences (ABC, BCA, CAB, ACB, CBA and BAC) where Treatment A was single oral dose of 900 milligrams (mg) pirtobrutinib, Treatment B was single oral dose of 900 mg pirtobrutinib matched placebo and Treatment C was single oral dose of 400 mg moxifloxacin.

Treatment Period 1 (Day 1)

Reasons for not completing this period:

Treatment Period 2 (Day 12)

Treatment Period 3 (Day 23)

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic/Corrected QT interval (PK/QTc) population included all participants who were in both the PK and QT/QTc populations with at least 1 pair of post-dose PK and ΔQTc data from the same time point in at least 1 period as well as participants in the QT/QTc population who received placebo. As per planned analysis, data was planned to be reported only for Treatment A (900 mg pirtobrutinib) concentration for this outcome measure.

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 1 dose of study drug.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF), measured over Baseline (Predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose.

The primary endpoint was placebo-corrected change from baseline in QT interval corrected using Fridericia’s correction, expressed in milliseconds. The QT interval measures the time from the ECG Q wave to the end of the T wave, corresponding to electrical systole. Because the QT interval varies with heart rate, a correction is used to make measurements more comparable across heart rates. QTcF denotes correction using Fridericia’s method.

Change from baseline describes how a measurement changes after dosing relative to its predose value. Subtracting or otherwise adjusting for the placebo response is intended to isolate the treatment-associated change from changes that may also occur without active treatment. The registry describes the placebo-corrected effect as model-predicted. It reports least-squares means as the endpoint measure and a 90% confidence interval as the dispersion measure.

QTc is used in cardiac safety assessment because changes in ventricular electrical repolarization can be relevant to evaluating a drug’s potential cardiac effects. The registry describes ECGs extracted from continuous recordings at prespecified time points. Participants rested supine before and after each ECG extraction. Measurements were scheduled from baseline through 24 hours post-dose. The primary endpoint estimates and confidence intervals at the specified time points are not reported in the registry record, so the magnitude and precision of the observed QTcF effect cannot be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a placebo-corrected change represent?

Change from baseline compares a post-dose measurement with a predose measurement. A placebo-corrected change then contrasts the treatment-associated change with the change under placebo. In general, this approach helps distinguish a drug-associated signal from time-related changes, measurement variation or other changes that also occur during a study. The registry says the endpoint was calculated from a model-predicted effect. It does not report the model specification or numerical estimates.

What is QTcF?

The QT interval changes with heart rate, so a correction formula is applied. The primary endpoint used Fridericia’s correction, denoted QTcF. The registry also lists secondary measures involving heart rate, pulse rate, QRS intervals, and alternative heart-rate corrections if a substantial heart-rate effect was observed. These are described as planned outcome measures, but their results are not reported in the registry record. In general, looking at related ECG measures can help characterize whether an observed QTc change is accompanied by changes in heart rate or other electrical intervals; no such pattern can be assessed from this record.

What does a least-squares mean convey?

A least-squares mean is an estimate derived from a statistical model rather than simply an arithmetic average of the observed values. In general, model-based estimates can account for factors included in the model and can express the comparison of interest on a consistent basis. Their interpretation depends on which terms and assumptions the model uses. The registry identifies least-squares means but does not report the model terms, covariance structure, estimation details or diagnostics. Readers therefore cannot assess from the record how the model represented the crossover measurements or handled within-participant correlation.

How should the confidence interval be read?

The registry names a 90% confidence interval as the dispersion measure for the primary endpoint. In general, a confidence interval communicates uncertainty around an estimated effect, conditional on the statistical method and its assumptions. It is not a guarantee that the true effect lies within a particular calculated interval, and it does not by itself establish clinical importance. The actual interval limits are not reported in the registry record. Without the limits and point estimates, no conclusion about precision or compatibility with particular effect sizes can be made.

Why is repeated measurement relevant?

ECGs were obtained at baseline and at multiple post-dose times, with measurements scheduled through 24 hours. Repeated measurements can describe how an effect changes over time rather than reducing the assessment to a single post-dose observation. In general, repeated measurements from the same participant are related, so the analysis should account for that dependence. The record does not report the model’s handling of repeated measurements, its selection of time points for inference, or whether any time-point-specific comparisons were adjusted for multiplicity.

What does a crossover design contribute?

In general, crossover studies compare treatments using observations collected from the same participants in different treatment periods. This can make each participant serve as a reference for their own measurements and may reduce variability from stable participant characteristics. The interpretation relies on suitable treatment sequencing and consideration of period effects, carryover and missing periods. The record identifies a 3-way crossover but does not report the sequences, washout details or analytical checks for these issues. No assumptions about how they were handled should be inferred.

What is the role of the positive control?

The study title identifies moxifloxacin as a positive control. In general, a positive control is included to help demonstrate that a study can detect an effect relevant to the measurement system. This role is distinct from the primary pirtobrutinib-versus-placebo question. The registry record does not report the positive-control endpoint estimate or an assay-sensitivity conclusion, so the control’s observed performance cannot be evaluated.

Overall, the listed methods identify the endpoint scale, correction, summary measure, confidence level and measurement schedule. They do not provide the model details or results needed to reproduce or fully assess the analysis. No p-values, estimates, confidence interval limits, analysis diagnostics or detailed statistical plan are reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint was measured at baseline and at scheduled post-dose times through 24 hours. The registry also lists secondary ECG outcomes, including changes in QTcF, heart rate, pulse rate and QRS intervals, plus alternative QT corrections conditional on a substantial heart-rate effect. Multiple outcomes and repeated time points can create multiple opportunities to identify an apparently notable result. In general, a prespecified multiplicity strategy helps clarify how such results should be interpreted and how statistical error is controlled across comparisons.

The registry record does not report a multiplicity adjustment, a hierarchy of hypotheses, a primary time point or a rule for interpreting the family of time-specific comparisons. It does not report whether the 90% confidence intervals were used descriptively or as part of a formal decision procedure. No analyses or primary outcome estimates are reported, so the impact of multiplicity cannot be assessed from the posted results.

The primary population description refers to participants in the PK and QT/QTc populations with at least one paired post-dose PK and ΔQTc observation at the same time point in at least one period, as well as participants in the QT/QTc population who received placebo. The description is incomplete at its end. The record does not provide a complete accounting of the analysis populations, exclusions, missing ECG observations, missing periods or the method used to handle missing data.

In general, missing measurements matter when the probability of missingness is related to treatment, participant characteristics or the unobserved outcome. The analysis method and assumptions used to address missingness affect interpretation. Those details are not reported in the registry record, and no assumptions about them can be made.

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 lists serious adverse event counts separately from other adverse events for each treatment group. The serious adverse event count is 0 in the 900 mg pirtobrutinib group, 0 in the matched-placebo group and 0 in the 400 mg moxifloxacin group. Deaths are listed as 0 in each group. The number at risk for the serious-event listing is 30, 31 and 30, respectively.

For other adverse events, the affected counts are 6 for pirtobrutinib, 1 for matched placebo and 1 for moxifloxacin. The corresponding numbers at risk are 30, 31 and 30. These are the registry’s group-level counts; they are not a comparison adjusted for the crossover design, treatment sequence or exposure time. No rates should be inferred from these counts without appropriate denominators and analysis.

Zero reported serious adverse events does not mean that no adverse effects of any kind occurred: the registry separately lists other adverse events. The record does not include serious adverse event terms, other adverse event terms, severity, timing, relationship to treatment or individual participant-level details. These safety counts are descriptive and do not answer the primary QTcF question.

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

The registry record describes a controlled study designed to assess the effect of pirtobrutinib on QTcF in healthy participants. It specifies a placebo-corrected endpoint, a measurement schedule, and the use of placebo and moxifloxacin in a crossover design. It also provides limited group-level adverse-event counts. These details explain the study question and some of the measurements used to address it.

The record does not report the primary endpoint estimates or their 90% confidence intervals. It also lists no analyses. Therefore, the posted information does not establish the direction or magnitude of the pirtobrutinib-associated QTcF change, how precisely it was estimated, or how it compared with placebo at the scheduled time points. The presence of a positive control in the design does not by itself show that the control produced a detectable response; its results are not reported.

In general, a QTcF estimate and confidence interval would describe an ECG measurement effect under the study’s analysis, not every aspect of cardiac safety. Interpretation would depend on the size and precision of the effect, the timing of measurements, the analysis assumptions and the broader safety evidence. Those statistical results and supporting details are not reported in the registry record.

The safety counts show that the registry lists no serious adverse events and no deaths in the treatment groups, while also listing other adverse events. They should not be read as proof that treatment has no safety risks, nor do they indicate how events were distributed by timing or severity. The study involved healthy participants and its stated primary focus was a cardiac electrophysiology measure, so the record does not provide a basis for conclusions about clinical benefit or treatment effectiveness in people with a disease.

The defensible interpretation is limited: the registry documents the study design and planned measurements, but the primary statistical results needed to answer its central question are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial matters statistically because it illustrates how a clinical question can be framed around a carefully specified physiological endpoint without the registry record necessarily containing the numerical result needed to answer it. The primary measure is not simply a raw QT interval: it is corrected for heart rate, expressed as change from baseline, contrasted with placebo and estimated using a model. Each step defines a different part of the estimand and requires clear reporting for readers to understand the result.

The crossover design also makes the analysis structure important. Repeated measurements from the same participant can be informative, but they require methods that account for dependence and treatment period. Reporting the treatment sequences, model assumptions and handling of incomplete observations would help readers assess whether the statistical approach aligns with the design. These details are not reported in the registry record.

The confidence interval is central to understanding precision, not an optional embellishment to a point estimate. Yet the record gives the confidence level without the interval limits or the estimate itself. This means readers cannot distinguish a small, precisely estimated effect from an uncertain result. The record also names a positive control, but does not report the control’s endpoint findings, leaving its contribution to interpretation unclear.

Finally, the distinction between an absent result and a null result is essential. The registry record does not report the primary outcome analysis; that is not evidence that the observed effect was zero or that a particular hypothesis was supported. Transparent outcome reporting is necessary for valid interpretation, synthesis with other evidence and evaluation of the study’s statistical claims.

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 principal limitation for statistical interpretation is that the primary endpoint results are not reported in the registry record. Neither the least-squares mean estimates nor their 90% confidence interval limits are available, and the registry lists no analyses. The effect’s direction, magnitude and precision therefore cannot be evaluated.

The record identifies a model-predicted endpoint but does not describe the model specification, included terms, correlation structure, diagnostics or handling of repeated measurements. It does not report the treatment sequences, washout details, or assessment of period and carryover effects. These omissions matter in a crossover study because design features and model choices affect how treatment comparisons are interpreted.

The primary population description is incomplete, ending after the text “A”. Further details about population eligibility and analysis membership are not reported in the registry record. Missing-data counts, reasons for missingness, exclusions and methods for handling incomplete periods are also not reported. The multiplicity approach for the repeated time points and secondary outcomes is not reported.

The registry lists limited adverse-event counts but does not provide event terms, severity, timing, treatment attribution or detailed follow-up. The primary outcome population is described in relation to PK and QT/QTc data, but the record does not report how many participants contributed to each time-point estimate. The registry also does not provide detailed findings for the pharmacokinetic, secondary ECG or broader safety aims. These limits prevent a complete assessment of the results and their robustness.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Effect of Pirtobrutinib (LOXO-305) on QTc Interval in Healthy Participants — NCT06215521.
• Registry record last updated 2025-02-24; status last verified 2025-01.
• Results first posted 2025-02-24.
• 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

NCT06215521 is a completed Phase I randomized, partially double-blind, 3-way crossover study sponsored by Eli Lilly and Company. It enrolled 31 healthy participants and compared pirtobrutinib with matched placebo and moxifloxacin. The primary endpoint was model-predicted placebo-corrected change from baseline in QTcF, summarized as least-squares means with 90% confidence intervals.

The registry describes ECG measurement timing and a PK/QTc analysis population, but the primary estimates, confidence interval limits and statistical analyses are not reported in the registry record. The adverse-event listings show 0 serious adverse events and 0 deaths in each treatment group, with other adverse-event counts of 6 for pirtobrutinib, 1 for matched placebo and 1 for moxifloxacin. The available record supports a description of the trial design and reporting gaps, but not a conclusion about the primary QTcF effect.