Relative Bioavailability Study of Nirmatrelvir/Ritonavir 4 Different Fixed Dose Combination Tablets Relative to the Commercial Tablets in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Relative Bioavailability Study of Nirmatrelvir/Ritonavir 4 Different Fixed Dose Combination Tablets Relative to the Commercial Tablets in Healthy Participants (NCT05525910), a randomized phase 1 study. The primary outcome is AUCinf of Nirmatrelvir Following the Administration of 4 Different Nirmatrelvir/Ritonavir FDC Tablets (Test Formulations) Compared to the Nirmatrelvir/Ritonavir 300(2*150)/100 mg Tablets (Reference Formulation).

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, single-dose crossover study in healthy adult participants under fasted conditions. Its stated purpose was to estimate the relative bioavailability of nirmatrelvir/ritonavir from four fixed-dose combination tablet formulations relative to the commercial tablet formulation. The registry record reports enrollment of 15 and a completed status. The listed study dates are 2022-08-31 for study start and 2022-11-07 for primary completion.

The commercial reference was Nirmatrelvir/Ritonavir 300(2*150)/100 mg. The four test formulations were 2*(150/50 mg) Low Disintegrant, 2*(150/50 mg) High Disintegrant, 2*(150/50 mg) HDL, and 3*(100/33.3 mg). The design is described as crossover, so the comparisons are framed around participants receiving different treatment formulations across the study. The record does not report the allocation sequence, the timing between treatment periods, or the precise scheduling of each dose. These details should not be inferred from the design label alone.

Open-label means that masking was not used, as reflected in the registry’s masking entry of none. The primary endpoint is AUCinf for nirmatrelvir. The analysis population is described as participants who took at least one dose and had at least one primary pharmacokinetic parameter reported. The posted formulation-level AUCinf summaries include 11 participants for the reference, Low Disintegrant, and High Disintegrant formulations, and 12 for the HDL and 3*(100/33.3 mg) formulations. The reason for these varying counts is not reported in the registry record.

The design is suited to estimating relative exposure after single doses, but the registry record does not report a full statistical model or its assumptions. It also does not report a sample-size justification. The listed enrollment should therefore be read as the number enrolled, not as evidence that a particular power target was met.

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 15 participants were randomized and assigned to receive the study intervention.

Period 1

Period 2

Period 3

Period 4

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported.

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 were enrolled in the study.

6. Primary Endpoint

The registry lists the primary outcome as AUCinf of Nirmatrelvir Following the Administration of 4 Different Nirmatrelvir/Ritonavir FDC Tablets (Test Formulations) Compared to the Nirmatrelvir/Ritonavir 300(2*150)/100 mg Tablets (Reference Formulation), measured over 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 1 of each treatment period.

The primary endpoint is AUCinf of nirmatrelvir, measured in nanogram*hour per milliliter (ng*hr/mL). AUCinf is the area under the plasma concentration-time profile from time 0, extrapolated to infinite time. In general, an area-under-the-curve measure summarizes drug exposure over time; the extrapolated endpoint also uses information about the terminal part of the concentration-time profile.

The registry describes AUCinf as AUClast + (Clast/kel). Clast is the predicted plasma concentration at the last quantifiable time point from a log-linear regression analysis, and kel is the terminal phase rate constant calculated by linear regression of the log-linear concentration-time curve. The listed sampling times run from pre-dose through 72 hours post-dose on Day 1 of each treatment period. The registry record does not report further details about the assay or the calculations beyond this definition.

Geometric means are reported for the formulation summaries, with geometric coefficients of variation as the dispersion measure. In general, geometric summaries are used for positive measurements that are analyzed on a multiplicative scale. The primary comparisons are ratios of adjusted geometric means, which express relative exposure between a test formulation and the commercial reference. A ratio near 100% represents similar estimated geometric means on this scale; the confidence interval communicates uncertainty around the estimate. No clinical outcome is measured by this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover design mean?

In general, a crossover study has participants receive more than one treatment condition, allowing comparisons between formulations to draw on measurements from the same participant. This can help account for some stable differences between people when estimating a treatment contrast. The registry labels this study randomized and crossover, but does not describe the sequence assignment, the number of periods, or the time between doses. It is therefore not possible to verify from this record how those design features were implemented or handled in the analysis.

The record also does not report the statistical model used for the primary comparisons. In a crossover analysis, a model may need to account for within-participant measurements and for design factors such as treatment and period. That is a general consideration, not a description of the model used in this study. The analysis method field for the posted comparisons is not specified.

How should geometric means and ratios be read?

The posted primary summaries use geometric means and geometric coefficients of variation. In general, a geometric mean is suited to positive measurements when relative changes are of interest and the analysis is conducted on a logarithmic scale. A ratio of geometric means compares the estimated levels on that multiplicative scale. The posted comparisons are ratios of adjusted geometric means, expressed as percentages, for each test formulation against the commercial reference.

A ratio of 100% corresponds to equal adjusted geometric means. A ratio above or below that value indicates that the estimated geometric mean for the test formulation is above or below the reference on the ratio scale. This description concerns the estimate, not a clinical judgment. The registry does not report an acceptance range, an equivalence margin, or a stated hypothesis for interpreting the ratios, so none should be imposed on the results.

In general, the geometric coefficient of variation describes the relative spread of the observations on a geometric scale. It differs from a confidence interval: the coefficient summarizes variability among measurements, while a confidence interval describes uncertainty in an estimated quantity. The arm summaries report the former; the comparison analyses report the latter for the ratios.

What information does the confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the observed data under the analysis procedure and its assumptions. A wider interval indicates less precision than a narrower interval, though width should be interpreted in context. The posted intervals are 90% confidence intervals. They provide uncertainty bounds around the ratios, not a probability that a particular value is true. They also do not establish whether a formulation meets a criterion, because the registry record does not report a criterion.

All four posted intervals include 100%. This means that equal adjusted geometric means are among the values encompassed by each reported interval. The ranges also include values above and below 100%, showing that the estimates are compatible with different relative-exposure values. This is a statement about statistical uncertainty, not a conclusion about clinical benefit, safety, or interchangeability.

How was AUCinf constructed?

The registry defines AUCinf as the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. It reports the calculation as AUClast + (Clast/kel). Clast is the predicted plasma concentration at the last quantifiable time point from log-linear regression, while kel is the terminal phase rate constant calculated using linear regression of the log-linear concentration-time curve. In general, this construction combines observed exposure through the last quantifiable measurement with an extrapolated terminal component.

The listed time points extend from pre-dose to 72 hours after dosing on Day 1 of each treatment period. The record does not provide the proportion of AUCinf that was extrapolated, participant-level concentration profiles, or rules for handling parameters that could not be estimated. Those details can matter when assessing the reliability of an extrapolated exposure measure, so they cannot be evaluated from the posted summary alone.

What is not specified about the analysis?

The record reports 24 analyses overall and 11 outcome measures. It lists the AUCinf comparisons, but does not identify the model, covariates, treatment sequence handling, or method used to calculate the adjusted geometric means and confidence intervals. The method field is not specified. The record also does not report a prespecified statistical analysis plan, the sample-size justification, interim analyses, or the handling of missing observations. These omissions limit independent assessment of the analysis choices.

In general, over-dispersion means that variability is greater than a statistical model expects. If it is present and not adequately accounted for, uncertainty estimates can be unreliable. The registry summaries include geometric coefficients of variation, but do not report a model assessment for over-dispersion or a method for addressing it. This general issue should not be mistaken for evidence that over-dispersion occurred in this study.

Any sample-size figures elsewhere on the page are planning illustrations based on stated assumptions, not observed power and not the trial’s own design justification. They do not change what the posted data show. The registry record does not report the rationale used to choose enrollment or the number of participants needed for a target level of precision.

10. Analyses Reported by the Sponsor

The registry’s own analysis reports adjusted geometric mean ratios and 90% confidence intervals for each test formulation against the commercial reference. Those are the primary comparison results to use when describing the sponsor’s reported analysis. The record does not specify the statistical method behind the adjusted estimates, so the adjustment procedure cannot be reconstructed from the posted information.

The registry record flags no discrepancy between a sponsor result and a recalculation. It also indicates that two-arm comparisons could not be reduced to one comparison for this outcome type. As a result, there is no separately reported recalculated comparison to place beside the sponsor’s results. The arm-level geometric means and coefficients of variation are descriptive summaries; they should not be substituted for the adjusted ratios or treated as an independent reconstruction of them.

Where a recalculation differs from a sponsor analysis, the sponsor’s own analysis takes precedence. That situation is not indicated. The main limitation is instead that the record does not give enough method detail to independently reproduce the adjustment or evaluate the model. The reported ratios and confidence intervals therefore provide the available inferential results, with the stated uncertainty and the method reporting limitation kept in view.

11. Multiplicity, Missing Data and Analysis Populations

The record lists 11 outcome measures and 24 analyses overall. Five secondary outcomes are described: participant counts with all-causality and treatment-related TEAEs; clinically significant laboratory abnormalities in hematology, chemistry, and urinalysis; clinically significant changes from baseline in vital signs; clinically significant physical examination values; and clinically significant abnormal 12-lead ECG findings. The primary outcome is AUCinf of nirmatrelvir, compared across four test formulations with the commercial reference.

With multiple outcomes or comparisons, the chance of at least one apparently unusual result can increase if each is assessed separately. In general, multiplicity procedures can control or otherwise address this issue, depending on the scientific aim. The registry record does not report whether a multiplicity adjustment was planned or applied, how the 24 analyses relate to the listed outcomes, or whether the four primary comparisons were treated as one family. No adjustment should be assumed.

The reported analysis population includes participants who took at least one dose and had at least one primary pharmacokinetic parameter reported. The record does not specify how missing measurements were handled, whether participants were excluded from particular comparisons, or why the AUCinf summaries have different participant counts. It does not report an imputation method, a sensitivity analysis for missing data, or a detailed account of analysis-population exclusions.

In general, missing-data methods can affect estimates when the availability of measurements is related to participants’ outcomes or treatment experience. The posted counts alone do not reveal why a measurement is absent or whether missingness could affect the comparisons. The registry record also does not report interim analyses or a statistical analysis plan that would clarify prespecified outcome hierarchy, multiplicity handling, or missing-data procedures. These gaps limit the ability to assess the full inferential framework from the registry record.

12. 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 posted safety figures list no serious adverse events in any of the five formulation groups. The numbers at risk were 11 for the reference, Low Disintegrant, and High Disintegrant formulations, and 12 for HDL and 3*(100/33.3 mg). The registry also lists other adverse events affecting 2 participants in the reference group, 0 in Low Disintegrant, 2 in High Disintegrant, 1 in HDL, and 2 in 3*(100/33.3 mg). No deaths are listed.

These are counts in small groups, not estimates of comparative risk with a precision measure. The record does not report confidence intervals for the safety counts or a formal comparison between formulations. It also does not provide event terms in the posted serious-event listing. The secondary outcome description includes both all-causality and treatment-related TEAEs, but the group-level figures alone do not establish which of the listed other events were treatment-related. Zero serious events in these groups should be read as an observation in this study, not as evidence that serious events cannot occur.

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

The results describe how nirmatrelvir AUCinf after four test tablet formulations compared with the commercial reference in healthy adults after single dosing under fasted conditions. The posted adjusted geometric mean ratios range from 100.72% to 110.45%, and each is accompanied by a 90% confidence interval. The intervals all include 100%, while also extending to values on both sides of that reference point. The data therefore leave uncertainty around the relative exposure estimates.

These findings do not establish equivalence, because the registry record does not report an equivalence margin or a decision criterion. A confidence interval that includes 100% is not, by itself, proof that two formulations are equivalent. Nor does an interval spanning 100% establish that there is no difference. It describes the range of values compatible with the data and analysis procedure, under the method’s assumptions.

The trial’s scope also matters. It assessed pharmacokinetic exposure for nirmatrelvir, rather than clinical outcomes. It involved healthy adult participants, a single dose, and fasted conditions. The record does not provide results for repeated dosing or for a patient population. The posted AUCinf findings should not be extended beyond the setting studied.

The available safety counts are likewise limited observations from the study groups. They do not provide a reliable basis for broad conclusions about comparative safety, particularly because the groups are small and no comparative safety analysis is posted. More generally, the registry record does not supply enough detail to assess all statistical model choices, missing-data handling, or multiplicity procedures. The proper reading is descriptive and conditional: these are the posted estimates and uncertainty intervals for the stated endpoint, in the stated study setting.

14. Why This Trial Matters Statistically

This study illustrates why a relative bioavailability result should be read through both its estimate and its uncertainty. A ratio summarizes the relative geometric means, while the confidence interval shows the range of values compatible with the analysis. Looking only at the point estimate would conceal how much uncertainty remains; looking only at whether an interval includes 100% would also be too simple, particularly when the registry does not report a decision threshold.

The crossover design is statistically relevant because, in general, within-participant comparisons can reduce the influence of stable differences between participants. But that potential depends on the study’s implementation and analysis. The registry identifies the randomized crossover design without reporting sequence, period, or model details. This is a useful distinction between knowing the broad design and knowing how its statistical structure was handled.

The record also demonstrates the importance of separating descriptive summaries from comparative estimates. The geometric means and coefficients of variation characterize the posted formulation-level data; the adjusted ratios and their confidence intervals are the reported comparisons. They answer related but different questions and should not be conflated.

Finally, the outcome is pharmacokinetic, and the study is described as a single-dose investigation in healthy participants under fasted conditions. Statistical interpretation should stay within that narrow scope. The posted results are informative about the measured exposure comparison, but they do not answer clinical-outcome questions. Reporting the analysis population and the incomplete method details helps readers judge what can be learned and where the record leaves uncertainty.

15. 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.

Several trial-specific limitations affect interpretation. The registry reports enrollment of 15, while the formulation-level AUCinf summaries include 11 or 12 participants. The reason for the differing counts is not reported in the registry record. The eligibility and analysis-population description identifies participants with at least one dose and at least one primary pharmacokinetic parameter reported, but does not explain exclusions or missing measurements in more detail.

The statistical method for the adjusted geometric mean comparisons is not specified. The record does not describe the model, the handling of the crossover structure, any covariates, or how the confidence intervals were obtained. It also does not report an equivalence margin or another formal criterion for interpreting the ratios. Consequently, the posted comparisons can be described, but the full analysis cannot be independently reconstructed from the registry record.

The record lists multiple outcomes and analyses but does not report a multiplicity strategy, interim analyses, or a statistical analysis plan. It does not report the sample-size justification. The number enrolled should not be read as evidence of adequate power or a targeted precision level.

For AUCinf, the registry gives the mathematical definition and sampling schedule, but does not report the degree of extrapolation, participant-level profiles, or the handling of parameters that could not be estimated. The safety information is also limited to group counts, without posted comparative uncertainty estimates. Finally, this was a single-dose study in healthy adult participants under fasted conditions. These features limit how far the pharmacokinetic and safety summaries can be generalized beyond the setting described.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Relative Bioavailability Study of Nirmatrelvir/Ritonavir 4 Different Fixed Dose Combination Tablets Relative to the Commercial Tablets in Healthy Participants — NCT05525910.
• Registry record last updated 2024-09-19; status last verified 2024-04.
• Results first posted 2024-09-19.
• 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.

19. Record Summary

NCT05525910 is a completed Phase 1 randomized, open-label, single-dose crossover study of four nirmatrelvir/ritonavir fixed-dose tablet formulations compared with the commercial tablet formulation in healthy adults under fasted conditions. The primary endpoint was nirmatrelvir AUCinf. The registry reports adjusted geometric mean ratios with 90% confidence intervals for each test formulation versus the reference. Every reported interval includes 100%, and the record does not state an equivalence criterion or a formal decision threshold.

The posted formulation summaries include 11 or 12 participants, compared with total enrollment of 15. The record does not explain the differing endpoint counts or specify key analysis details such as the statistical model, multiplicity approach, or missing-data handling. Safety counts list no serious adverse events or deaths in the groups, with other adverse events recorded in some groups. Findings should be interpreted as single-dose pharmacokinetic and safety observations in the study population and conditions described.