A Fixed-Sequence, Drug-Drug Interaction Study Between Multiple Oral Doses of Inarigivir Soproxil and a Single Oral Dose of Midazolam in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Fixed-Sequence, Drug-Drug Interaction Study Between Multiple Oral Doses of Inarigivir Soproxil and a Single Oral Dose of Midazolam in Healthy Subjects (NCT03493698), a non-randomized phase 1 study. The primary outcome is Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax).

2. Clinical Question

3. Trial Design

This was a Phase 1, open-label, non-randomized, fixed-sequence study in healthy subjects. The registry record describes it as a single-center study. Seventeen participants were enrolled, and the record lists the study as completed. Because treatment order was fixed and masking was absent, participants and study personnel were not blinded to the scheduled treatments.

The treatment sequence began with Treatment A: a single oral dose of 2 mg midazolam on Day 1. Treatment B and Treatment C are both described as inarigivir treatments, with a single oral dose of 400 mg listed for Day 3 and Day 6-18. Treatment D is described as a single oral dose of 400 mg inarigivir given with a single oral dose of 2 mg midazolam on Day 19. The record does not further explain the distinction between Treatments B and C or the exact dosing schedule across the listed days.

The primary comparison uses midazolam Cmax from Treatment A on Day 1 and Treatment D on Day 19, respectively. This sequence lets the study compare midazolam pharmacokinetics before and during the specified inarigivir regimen. It does not provide a concurrent group assigned to midazolam without inarigivir at the later time point. Treatment order was not randomized, so differences between the two measurement occasions could reflect both the differing treatment conditions and other time-related factors.

The adverse-event record lists 17 participants at risk for Treatments A and B, and 15 at risk for Treatments C and D. Those group counts indicate that the number at risk varied across the sequence, but the registry record does not explain why. It also does not report a participant-flow account or the number with evaluable primary pharmacokinetic data.

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: Each subject was expected to complete treatment groups A, B, C and D; sequentially.

Treatment Period A

Treatment Period B

Treatment Period C

Reasons for not completing this period:

Treatment Period D

Analysis population for the primary outcome, as defined in the registry: All subjects who received at least one dose of midazolam and had sufficient concentration-time data to reliably estimate PK parameters

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.

6. Primary Endpoint

The registry lists the primary outcome as Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax), measured over Day 1 Treatment A and Day 19 Treatment D, respectively.

The primary endpoint is midazolam Cmax, measured in ng/mL. Cmax is the maximum concentration observed in the blood after a dose. In a drug-interaction study, comparing this measure before and during another drug’s dosing can describe whether the concentration peak of the measured drug differs under the two specified conditions. Cmax is one part of a pharmacokinetic profile; it does not, by itself, describe the full concentration-time curve or every aspect of drug exposure.

The registry record specifies the mean as the reported summary and full range as the dispersion, with the comparison made between midazolam given on Day 1 in Treatment A and midazolam given on Day 19 in Treatment D. It describes the primary question as the effect of steady-state oral inarigivir on the single-dose pharmacokinetics of oral midazolam. The record’s endpoint description identifies Cmax as the measure of interest, but does not report a numerical mean, range, treatment comparison, or inferential result.

Using the same named pharmacokinetic measure at both occasions supports a direct description of the concentration peak under each scheduled condition. However, the registry record does not state how the comparison was statistically modeled or whether it used paired participant-level data. It also does not report a confidence interval or other measure of precision for the difference or relative change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a pharmacokinetic endpoint and a fixed-sequence design, but does not report the statistical method used to compare the measurements. The distinctions below explain what the endpoint and design imply in general; they should not be read as a description of an unreported analysis.

What does Cmax represent?

Cmax is the highest measured concentration after a dose. It is a summary of the concentration-time profile and can be relevant when a study asks whether another treatment changes the peak concentration. A measured Cmax depends on the sampling schedule and the quality of the concentration-time data. The record defines the primary population partly by whether there was sufficient concentration-time information to estimate pharmacokinetic parameters reliably, but it does not give the sampling schedule or the number of participants with evaluable profiles.

The registry specifies a mean and full range for Cmax. A mean describes the average of the measurements included in a summary, while the full range gives the lowest and highest reported values. A range shows the span of observed values, but does not by itself quantify the precision of a treatment comparison. It is also not a substitute for a confidence interval around an estimated contrast. The record does not provide the corresponding numerical summaries.

What does a fixed sequence imply?

In a fixed-sequence study, participants receive treatments in a planned order rather than being randomly assigned to different treatment orders. This study lists midazolam alone first and midazolam with inarigivir later. In general, measurements from the same participant at different times may be statistically related, which can be accounted for in a paired analysis. Whether a paired method was used is not reported in the registry record.

Because the two treatment conditions occur at different stages, the comparison may also be affected by time-related differences between occasions. Random assignment of treatment order can help balance such influences across groups, but this study is described as non-randomized and fixed-sequence. The registry record does not report a method for separating treatment-condition differences from period or sequence effects. The result, if available, would need to be interpreted in the context of that design rather than as a randomized treatment contrast.

How would uncertainty be assessed?

In general, an estimate describes the magnitude and direction of a comparison, while a confidence interval describes its precision under the assumptions of the analysis. A narrow interval indicates more precise estimation than a wide interval, though precision is distinct from whether an effect is important. A p-value, when reported, addresses compatibility of the data with a specified null model; it does not measure the size or importance of an effect. No estimate, interval, or p-value for the primary comparison is reported in this registry record.

Pharmacokinetic measurements can vary across participants and may have distributions that are not well represented by a simple symmetric model. General statistical approaches sometimes use transformations or models suited to skewed data, but the record does not say that any such approach was used. It also does not report whether the primary analysis compared arithmetic means, transformed measurements, or another parameterization. No method should be attributed to the study without that information.

What can the planning description tell us?

The registry record describes a planning illustration based on a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the detectable effect set as a stated fraction of an observed effect. It distinguishes participant counts per arm from total event counts in time-to-event examples. Those are general planning assumptions, not a report of the trial’s own design justification. The study itself is fixed-sequence rather than an equal-allocation randomized comparison, so such an illustration should not be mistaken for the design actually used.

Sample-size calculations based on an observed effect are hypothetical planning exercises. They do not show the probability that this completed study detected an effect, and they do not replace a reported estimate with an uncertainty interval. The registry record does not report the trial’s own sample-size justification, target enrollment rationale, or any resulting planning figures.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures and no analyses. It identifies Cmax as the primary outcome, and lists secondary outcomes relating to clinical laboratory, vital signs, 12-lead ECG, or physical examination findings, and inarigivir pharmacokinetics after single and multiple oral doses, including AUC and Cmax. The record does not report a statistical testing hierarchy, multiplicity adjustment, or which outcomes were analyzed. It is therefore not possible to assess how multiple outcome comparisons were handled.

The stated primary population consists of participants who received at least one midazolam dose and had enough concentration-time data to estimate pharmacokinetic parameters reliably. That definition does not give the number analyzed. The registry record does not report the number with measurements at both primary comparison occasions, the number excluded from the primary analysis, reasons for exclusion, or methods for handling missing observations and incomplete concentration-time profiles.

The record lists enrollment of 17, but enrollment is not necessarily the same as the analysis population. The adverse-event group counts show 17 at risk in Treatments A and B and 15 at risk in Treatments C and D; they do not establish the number included in the primary pharmacokinetic analysis. No imputation procedure, sensitivity analysis, or missing-data assumption is reported.

These omissions limit interpretation of the primary comparison: readers cannot establish from the registry record how many observations informed it, how missing data were treated, or whether the reported outcomes were adjusted for multiplicity. The record also does not report an analysis plan that would clarify these choices.

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 lists zero serious adverse events in each of the four treatment groups. The numbers at risk are 17 for Treatment A, 17 for Treatment B, 15 for Treatment C, and 15 for Treatment D. It also lists zero deaths in every group. No serious adverse-event terms are listed.

These are counts recorded for the specified groups, not estimates of the chance of a serious event in a broader population. The groups belong to a fixed sequence, and the numbers at risk are not the same for every treatment. The record does not provide an explanation for the change in numbers or a participant-flow account. It also does not report event timing, exposure-adjusted rates, or a comparison designed to estimate differences in serious-event risk.

A zero count in a study of this size does not establish that an event cannot occur. It means that no serious events were recorded in these groups in the registry data. The record also lists other adverse events: four participants for Treatment A, four for Treatment B, seven for Treatment C, and two for Treatment D. These counts are separate from the serious-event counts and do not answer the primary pharmacokinetic question.

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

The registry record establishes that the study was designed to compare midazolam Cmax after a single dose before inarigivir dosing and after a single dose given with inarigivir. It also describes the population, fixed treatment order, scheduled doses, and the intended primary pharmacokinetic measure. These details explain what the study set out to examine.

They do not establish the result of that comparison. The registry record does not report Cmax values, a treatment contrast, a confidence interval, or a statistical test result. It is therefore not possible to state from the record whether the measured concentration peak was higher, lower, or similar between the two occasions, or how precise any estimate was. The study objective is not itself a result.

The design also shapes what a result could mean. All participants followed a fixed order, with the two midazolam occasions separated in the study schedule. Without a concurrent randomized control and without reported analysis details, a difference between occasions could not automatically be attributed only to the presence of inarigivir. The registry record does not say how timing or within-participant correlation was addressed analytically.

The safety counts provide descriptive information about recorded adverse events during the listed treatments. They do not demonstrate the absence of risk, and they do not provide evidence about the size or precision of the pharmacokinetic comparison. The listed event counts should be read within the enrolled study population and the reported exposure periods.

Overall, the record describes a completed study and a clear primary question, but lacks the numerical outcome information needed to assess the observed pharmacokinetic comparison. No conclusion about the direction, magnitude, or statistical precision of a Cmax difference can be drawn from the information reported.

13. Why This Trial Matters Statistically

Drug-interaction studies often use pharmacokinetic measures to characterize how one treatment condition relates to concentrations of another drug. This study’s stated question focuses on midazolam Cmax after a single dose alone and after a single dose given with inarigivir. That focus makes the endpoint and dosing sequence important to understanding what the study was designed to measure.

Statistically, the fixed sequence highlights the distinction between a repeated measurement and a randomized comparison. Measurements at different occasions in the same participants may be related, while the treatment conditions are also tied to different points in the schedule. A sound interpretation depends on knowing how the comparison was modeled and how its uncertainty was quantified. Those analysis details and the primary numerical result are not reported in the registry record.

The record also illustrates why enrollment, endpoint definition, and outcome reporting answer different questions. The enrollment count describes the number enrolled, but not necessarily the number included in a pharmacokinetic analysis. Naming Cmax defines the measure, but does not give its observed values. Listing safety counts describes recorded events, but does not resolve the primary pharmacokinetic question. Each piece of information has a distinct role in evaluating evidence.

For clinical researchers and biostatisticians, the central statistical lesson is that a stated objective and a completed status do not establish what the data showed. Interpretation requires the estimate, a measure of uncertainty, the analysis population, and enough methodological detail to judge the comparison. Without these, the registry record supports understanding of the question and design, but not an assessment of the magnitude or precision of the primary outcome.

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 most important limitation for interpreting the primary question is that the registry record does not report the numerical Cmax results or an inferential comparison. There is no stated estimate, confidence interval, or test result. As a result, the direction, magnitude, and precision of the comparison cannot be assessed.

The design was non-randomized and fixed-sequence, with midazolam alone measured on Day 1 and midazolam with inarigivir measured on Day 19. Treatment condition is therefore linked to the timing and order of measurement. The record does not report whether the analysis accounted for within-participant correlation or addressed possible period effects. It does not identify a concurrent later-time control condition.

The record gives an enrollment of 17 and identifies a primary population based on dose receipt and sufficient concentration-time data, but does not report how many participants qualified or contributed observations at both time points. The adverse-event counts show fewer participants at risk in the later listed treatments than in the earlier ones, but the reason is not reported. Missing-data handling, exclusions, and sensitivity analyses are also not reported.

Other limitations in the available record include the absence of the statistical analysis method, a reported sample-size justification, and a multiplicity plan. The record lists six outcome measures and no analyses, leaving unclear which outcomes were analyzed and how any multiple comparisons were treated. These reporting gaps prevent a full assessment of the primary estimate, its reliability, and the scope of the conclusions that could be drawn.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Fixed-Sequence, Drug-Drug Interaction Study Between Multiple Oral Doses of Inarigivir Soproxil and a Single Oral Dose of Midazolam in Healthy Subjects — NCT03493698.
• Registry record last updated 2020-10-08; status last verified 2020-09.
• Results first posted 2020-10-08.
• 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

This completed Phase 1 study enrolled 17 healthy subjects and used an open-label, non-randomized, fixed sequence. The primary question concerned midazolam Cmax after a single oral dose on Day 1 and after a single oral dose given with inarigivir on Day 19. The registry record describes a mean and full range as the planned summary for the endpoint.

The record lists zero serious adverse events and zero deaths in each treatment group, with 17 participants at risk in Treatments A and B and 15 in Treatments C and D. It lists six outcome measures and no analyses. Numerical primary pharmacokinetic results, an uncertainty interval, the analysis method, and details on missing data are not reported in the registry record.