A Study to Investigate the Effect of Rifampicin on the PK of Multiple Doses of Balovaptin In Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Investigate the Effect of Rifampicin on the PK of Multiple Doses of Balovaptin In Healthy Volunteers (NCT03586726), a non-randomized phase 1 study. The primary outcome is Maximum Plasma Concentration (Cmax) for Balovaptan.

2. Clinical Question

This is a pharmacokinetic interaction question, not a comparison of clinical benefit between treatment groups. Cmax is the observed peak concentration of the analyte in plasma. The study’s within-subject structure means that the planned assessment concerns measurements from the same participants in different periods, rather than outcomes in separate randomized groups. That structure can make individual participants their own reference, but the registry record does not provide the numerical period results needed to determine the size or precision of any difference.

The record identifies safety and additional pharmacokinetic outcomes as well. It does not report the detailed dosing schedule, the primary endpoint results, or the analysis used to quantify the period contrast. Consequently, the research question can be described from the registered objective and endpoint, but the result itself cannot be characterized as an increase, decrease, or absence of change.

3. Trial Design

This completed Phase 1 study is registered as a single-center, non-randomized, open-label, one-sequence, two-period, within-subject study. The registry reports enrollment of 16 and identifies healthy volunteers as the study population. The study was conducted at one site in the Netherlands. Its listed start date is 2018-07-24, and its primary completion date is 2018-11-02.

The stated objective was to investigate the effects of multiple doses of rifampicin on the pharmacokinetics and safety of multiple doses of balovaptan. Participants received study drugs in two periods, with a washout between the last dose in Period 1 and the first dose in Period 2. The registry gives the washout as a minimum of 14 days to a maximum of 21 days. It does not report the exact period-by-period dosing schedule, dose levels, adherence information, or details of how the washout was implemented.

Non-randomized and open-label describe important features of how the study was organized. The record does not describe allocation to competing parallel groups or masking of participants or investigators. Instead, the one-sequence within-subject design focuses on observations across periods in the same study participants. That design is suited to a pharmacokinetic question, but period comparisons can also reflect changes over time or other period-related influences. The registry does not report an analysis plan addressing those influences.

The registry’s enrollment figure is not the same as a reported endpoint-specific analysis count. Although the population description refers to subjects who received at least one dose of balovaptan and notes exclusion criteria for the pharmacokinetic analysis, the final analysis population and the number contributing to each endpoint 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

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 Maximum Plasma Concentration (Cmax) for Balovaptan, measured over Day 10 of Period 1 and Day 16 of Period 2.

The primary endpoint is maximum plasma concentration, Cmax, for balovaptan. It is defined as the observed peak analyte concentration obtained directly from experimental data without interpolation, and is expressed in ng/mL. The specified assessment times are Day 10 of Period 1 and Day 16 of Period 2.

Cmax captures the highest measured plasma concentration during the relevant sampling period. In pharmacokinetic research, peak concentration helps characterize exposure and can be useful when asking whether another drug changes the concentration profile of a study drug. It complements measures that describe exposure across a longer interval, such as area under the concentration-time curve, which appears among the listed secondary outcomes for metabolites.

The registry specifies a geometric mean as the endpoint summary and a geometric coefficient of variation as the dispersion measure. A geometric mean summarizes positive measurements on a multiplicative scale; a geometric coefficient of variation describes relative variability on that scale. These summaries do not by themselves provide a comparison between periods. To interpret a period contrast, readers would need the reported values and an estimate of the contrast, with an indication of its uncertainty.

The record does not report the Cmax values, a ratio or other contrast, confidence intervals, or a significance test. Therefore, the endpoint definition and summary type are available, but the magnitude and precision of the observed period comparison are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a within-subject design compare?

In a within-subject design, measurements from the same participant are compared across conditions or periods. This differs from a parallel-group comparison, where different participants contribute to each treatment group. Because a participant’s characteristics that remain stable across periods are shared by their own measurements, within-subject comparisons can account for some between-person variability. This is a general statistical feature, not a claim about the size of any advantage in this study.

The record describes a single sequence and gives separate assessment days in Period 1 and Period 2. It also reports a washout interval of a minimum of 14 days to a maximum of 21 days. A washout is intended to separate treatment periods, but its presence alone cannot establish that carryover is absent. The registry does not report the period-specific dosing schedule, pharmacokinetic carryover assessment, or any method used to assess period effects.

What does the geometric mean describe?

The primary endpoint is summarized using a geometric mean, with geometric coefficient of variation as the dispersion measure. In general, geometric summaries are useful for positive measurements whose variation is more naturally described multiplicatively than additively. The geometric mean is obtained by working on a logarithmic scale and returning to the original scale. The coefficient of variation expresses dispersion relative to the geometric mean rather than in the measurement’s original units.

These summaries describe measurements within a condition. They do not alone quantify the comparison of interest. A period contrast might be expressed as a ratio or another prespecified contrast, but the registry record does not report the contrast format or analysis method. No particular model, transformation, adjustment, or inferential procedure should be presumed from the endpoint summary fields.

How should uncertainty be interpreted?

In general, a confidence interval describes a range of values compatible with the data and the statistical method used, while reflecting sampling uncertainty. A narrow interval indicates greater precision than a wide interval on the same scale. A point estimate without an interval cannot show how precisely an effect has been estimated. A p-value, when reported, addresses compatibility with a specified null hypothesis under an analysis model; it does not measure the probability that the null hypothesis is true or the clinical importance of an effect.

No confidence interval or p-value for the primary endpoint is reported in the registry record. Nor is a primary contrast estimate available. Thus, these inferential quantities cannot be interpreted for the study from the registry information. The absence of reported inferential results is not equivalent to a finding of no difference.

Why can variability matter?

Pharmacokinetic measurements can vary substantially between participants and may be right-skewed. In general, skewness can make methods based on symmetric, normally distributed errors unsuitable unless the data are transformed or analyzed with an appropriate model. Over-dispersion, meaning variability beyond what a simple model expects, can also make standard errors too small if ignored. These are general considerations; the registry record does not report a distributional assessment, a variance model, or a method for handling over-dispersion.

Repeated measurements also have a dependence structure: observations from the same participant are not generally independent. A valid analysis should account for that structure when estimating uncertainty. The registry identifies the within-subject design but does not describe the statistical model or the method used to account for within-participant correlation. It is therefore not possible to evaluate the model’s assumptions or reproduce the primary analysis from the registry record.

What do the planning assumptions mean?

The stated planning assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such calculations are planning aids: they estimate the sample size that would be needed under specified assumptions. They are not observed power, and they do not show what the completed study achieved.

The two-arm equal-allocation assumption differs from the registered one-sequence, within-subject design. A planning calculation built on that assumption should not be treated as a direct description of the study’s design or as a reconstruction of its own sample-size justification. The protocol’s sample-size justification is not reported in the registry record. The observed-effect input and numerical planning outputs are also not reported in the registry information summarized for this trial, so they cannot be evaluated.

The registry reports zero analyses. That entry does not mean that no participants were enrolled or that no measurements were made; it means that analyses are not listed in the registry results record. It also does not identify an inferential analysis to interpret. Without the analysis specifications and output, readers cannot determine whether the endpoint was analyzed as a paired contrast, whether adjustments were made, or how uncertainty was calculated.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary endpoint of balovaptan Cmax and reports 14 outcome measures. Named secondary outcomes include adverse events; Tmax for balovaptan and the M2 and M3 metabolites; and metabolite-to-parent ratios for M2 and M3 based on AUC0-24 and Cmax. The registry record does not give results for these outcomes in the information available for this analysis.

When a study examines multiple outcomes, time points, or statistical comparisons, the chance of at least one apparently notable result can increase if each is tested independently. General approaches include specifying a primary comparison in advance, adjusting significance thresholds, or treating secondary analyses as exploratory. Which approach was used, whether any multiplicity adjustment was planned, and whether analyses were prespecified are not reported in the registry record. The primary endpoint designation does not by itself disclose how multiplicity was handled across all outcomes.

Missing-data handling is also not reported. The record does not give endpoint-specific participant counts, reasons for missing measurements, imputation methods, or sensitivity analyses. These details matter because incomplete observations can affect the estimate and its uncertainty, particularly if missingness is related to treatment, exposure, or participant characteristics.

The pharmacokinetic population description says that subjects who received at least one dose of balovaptan were eligible for that analysis and notes exclusions for significant eligibility violations, significant protocol deviations, or other data-related circumstances. The description is incomplete in the registry record, and final analysis counts and the exact application of the exclusions are not reported. A detailed statistical analysis plan, interim-analysis information, and a sample-size justification are not reported in the registry record.

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 one group, BALOVAPTAN+RIFAMPICIN. For serious adverse events, 16 participants were at risk and 0 were affected; deaths were 0. For other adverse events, 16 were at risk and 15 were affected. These are counts as recorded, not estimates of comparative risk between randomized groups.

The group label and counts do not establish that an event was caused by a study drug. Adverse events can occur during a study without being attributable to the treatment, and attribution requires information not captured by these counts alone. The registry record does not provide serious-event terms in its listing, and the summary counts do not describe event timing, severity beyond the serious classification, duration, or clinical course.

Zero affected participants recorded for serious adverse events should be read narrowly: no serious adverse events are listed as affecting participants in this registry group. It does not prove that the risk is zero, particularly when the group is small and the record does not provide further event surveillance detail. The count of 15 affected by other adverse events likewise does not indicate how many events occurred, since a participant may experience more than one event. A comparison of safety between treatment conditions is not reported.

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

This study addresses a focused pharmacokinetic question: whether balovaptan exposure, represented by maximum observed plasma concentration, differed across periods in a study investigating multiple doses of rifampicin. Its one-sequence, within-subject structure is relevant to that question because measurements can be compared within participants. The registry also identifies additional pharmacokinetic measures and adverse events as outcomes.

The registry record does not report the primary endpoint’s measured values or a statistical contrast. It therefore does not establish the direction or size of a change in Cmax, nor the precision of an estimate. Without a reported interval or other uncertainty measure, readers cannot assess how compatible the data are with effects of different magnitudes. The missing result should not be interpreted as evidence that the treatments had no effect.

The study also does not provide a randomized parallel-group comparison. The fixed sequence and period structure mean that differences across periods could be entangled with time or other period influences. Whether the analysis addressed those issues is not reported. The record’s enrollment figure cannot substitute for the number of participants with complete primary endpoint measurements, which is also not reported.

The adverse-event counts describe events recorded in the registry group, including zero participants affected by serious adverse events and zero deaths. They do not establish causality, and the listed counts are not a comparative safety estimate. The record’s safety summary and its absent pharmacokinetic result answer different questions and should not be conflated.

Accordingly, the record supports a description of the study question, design, endpoint definition, and selected adverse-event counts. It does not support a numerical conclusion about the pharmacokinetic interaction, a conclusion about clinical benefit, or a broad safety conclusion. Those judgments would require outcome estimates, uncertainty, analysis-population details, and fuller safety reporting that are not reported in the registry record.

13. Why This Trial Matters Statistically

Drug-interaction studies ask whether one drug changes the body’s handling of another. Pharmacokinetic endpoints such as Cmax make that question measurable by focusing on a concentration reached after dosing. For clinical researchers, the endpoint definition matters: a peak concentration captures a different feature of exposure from a measure integrated across time, and results from different pharmacokinetic measures are not interchangeable.

The within-subject design is statistically important because it makes the participant, rather than a separate group, the basis for the period comparison. This can reduce the influence of stable differences between people. However, that benefit depends on an appropriate analysis and careful consideration of period and sequence effects. The registry record identifies the design but does not report the analysis model or enough period-specific dosing detail to evaluate those issues.

This trial also illustrates why a registered endpoint is not the same as an interpretable result. The endpoint, units, summary measure, and timing are described, yet the primary values and uncertainty are not reported in the registry record. Without those elements, statistical interpretation cannot move from a clear research question to a quantified answer. A null conclusion cannot be inferred from a missing estimate.

Finally, safety counts need a different reading from pharmacokinetic summaries. Counts of participants affected provide a descriptive signal, but without event-level detail or a comparison condition they cannot establish attribution or comparative risk. Separating design, outcome definition, estimation, uncertainty, and safety reporting helps keep conclusions proportional to what the record actually documents.

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 central limitation for interpreting this trial from the registry record is that primary Cmax results are not reported. No period-specific geometric means, treatment contrast, confidence interval, or p-value is available. The effect’s direction, magnitude, and precision therefore cannot be assessed.

The record does not specify the exact dosing schedule for each period, dose levels, or the full timing and collection schedule for pharmacokinetic samples. It gives the primary assessment days and washout range, but these details alone are insufficient to reconstruct the exposure comparison or evaluate potential carryover. The statistical model and treatment of period effects are not reported.

Although enrollment is listed as 16, the endpoint-specific analysis population, missing measurement counts, and reasons for exclusion or missingness are not reported. The pharmacokinetic population description is incomplete, limiting assessment of who contributed to the results. The registry also reports zero listed analyses, so no analysis output is available to check against the endpoint definition.

The study was non-randomized, open-label, single-center, and conducted in healthy volunteers. These design characteristics limit what can be concluded from a period comparison and how directly the study population represents other settings. The registry does not report a randomized control group. The stated planning assumptions use equal allocation between two arms, which does not match the registered within-subject design; the study’s own sample-size justification is not reported.

For safety, the registry provides summary counts but no serious-event terms, event-level descriptions, or comparative analysis. These omissions prevent assessment of event characteristics and attribution. Taken together, the available record describes the study’s intent and selected design features but does not provide enough outcome or analysis detail for a full appraisal of the primary result.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Investigate the Effect of Rifampicin on the PK of Multiple Doses of Balovaptin In Healthy Volunteers — NCT03586726.
• Registry record last updated 2019-11-07; status last verified 2019-10.
• Results first posted 2019-11-07.
• 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

NCT03586726 is a completed Phase 1, single-center, non-randomized, open-label, one-sequence, two-period within-subject study in healthy volunteers. The registry reports enrollment of 16 and a study site in the Netherlands. It investigated the effect of multiple doses of rifampicin on the pharmacokinetics and safety of multiple doses of balovaptan.

The primary endpoint was balovaptan Cmax, summarized by geometric mean with geometric coefficient of variation, at Day 10 of Period 1 and Day 16 of Period 2. A washout of a minimum of 14 days to a maximum of 21 days is reported between periods. The primary endpoint results and statistical contrast are not reported in the registry record.

The safety listing reports 0 participants affected by serious adverse events, 15 affected by other adverse events, and 0 deaths in the listed group. The registry reports 14 outcome measures and zero analyses. Final analysis counts, missing-data methods, multiplicity handling, and the study’s sample-size justification are not reported in the registry record.