A Study Investigating the Absolute Oral Bioavailability of Balovaptan After Single and Multiple Daily Oral Doses of Balovaptan in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Investigating the Absolute Oral Bioavailability of Balovaptan After Single and Multiple Daily Oral Doses of Balovaptan in Healthy Volunteers (NCT03764449), a non-randomized phase 1 study. The primary outcome is Absolute Bioavailability of Oral Balovaptan at Dose Level A (Cohort 1).

2. Clinical Question

3. Trial Design

This was a completed Phase 1 study of balovaptan in healthy volunteers. The registry describes it as single-center, non-randomized, open-label, parallel-group, and involving two treatments. It lists an enrollment of 16 and reports that the study was conducted at one site in the Netherlands. The recorded start date is 2019-01-10, and the primary completion date is 2019-03-04.

The interventions were oral balovaptan and IV balovaptan. Cohort 1 received study drug at dose level A in two periods, while Cohort 2 received study drug at dose level B in two periods. For both cohorts, the record specifies a minimum washout period of 14 days between Day 1 of Period 1 and Day 1 of Period 2. The primary endpoint concerns absolute oral bioavailability at dose level A in Cohort 1; the listed secondary outcomes include bioavailability at dose level B and other pharmacokinetic measures, including maximum plasma concentration and time to maximum observed plasma concentration.

Non-randomized allocation means that treatment assignment was not described as random. Open-label means the record does not describe masking. These features matter when interpreting comparisons: the design should not be read as a randomized, blinded comparison of otherwise interchangeable groups. Although the record identifies parallel groups and two treatments, the detailed administration sequence and the precise participant-level relation between oral and IV dosing are not reported in the registry record. The stated cohort and period descriptions therefore define the available design information, but do not establish additional protocol details.

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: Participants in this study included healthy volunteers.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The Pharmacokinetic (PK) analysis population consisted of all participants 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 Absolute Bioavailability of Oral Balovaptan at Dose Level A (Cohort 1), measured over Day 1 of Period 1 (Period 1 is 14 days)..

The primary endpoint is titled “Absolute Bioavailability of Oral Balovaptan at Dose Level A (Cohort 1).” It concerns the absolute oral bioavailability of a single dose A of balovaptan on Day 1 of Period 1. The unit is percentage, and the endpoint is characterized by a geometric mean with geometric coefficient of variation as the dispersion measure. The registry record does not report the numerical estimate or its variability.

General: Absolute bioavailability describes the extent to which a drug given by a particular route reaches the systemic circulation, relative to an intravenous reference. An IV dose enters the circulation without the absorption step required for an oral dose, making the routes useful for assessing how much exposure follows oral administration relative to IV administration. Pharmacokinetic measurements of drug exposure support this comparison.

A percentage scale makes the endpoint interpretable as a relative amount rather than as a concentration alone. A geometric mean is commonly used for pharmacokinetic quantities that are positive and may vary multiplicatively; it summarizes values on a log scale before returning them to the original scale. The geometric coefficient of variation describes variability in that multiplicative setting. These are general interpretations of the statistical measures, not a substitute for the missing endpoint estimate. Without the reported result and its uncertainty, the registry record does not establish the size or precision of the bioavailability estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a pharmacokinetic study whose primary endpoint is absolute oral bioavailability at dose level A in Cohort 1. The endpoint is expressed as a percentage and summarized with a geometric mean and geometric coefficient of variation. The record does not provide the calculation details, the numerical estimate, or an inferential analysis result. The statistical concepts below explain how these measures are generally used; they do not assert that a particular unreported procedure was applied.

Why use an intravenous reference?

General: Oral administration requires a drug to be absorbed before it reaches systemic circulation. Intravenous administration bypasses that absorption step. Comparing exposure after oral and IV administration can therefore characterize the extent of oral availability relative to the IV reference. In practice, interpretation depends on the administered doses, pharmacokinetic measurements, and analysis details. The registry record names both oral and IV balovaptan but does not report the complete dose and calculation information needed to reproduce the bioavailability estimate.

What does a geometric mean describe?

General: A geometric mean is useful for positive measurements that are more naturally compared proportionally than by absolute differences. The method takes logarithms of the measurements, averages them on that scale, and transforms the average back. This gives a summary that is less dominated by very large values than an arithmetic mean can be when data are right-skewed. Pharmacokinetic concentrations and exposure measures often have this multiplicative structure. The geometric mean is a summary of the observed measurements, not a measure of how uncertain the estimated mean is by itself.

What does the geometric coefficient of variation add?

General: The geometric coefficient of variation describes dispersion on a multiplicative scale. It complements the geometric mean by conveying how variable individual measurements are relative to the central value. It is not interchangeable with a confidence interval: the coefficient describes variability among measurements, whereas an interval estimates uncertainty around a population parameter under a specified analysis. The registry names geometric coefficient of variation as the dispersion measure but does not report its value or provide the underlying participant-level data.

What can a confidence interval tell a reader?

General: A confidence interval expresses the range of values compatible with the data under a statistical procedure and its assumptions. Its width conveys precision, while its location conveys the range of effect or quantity estimates supported by the analysis. An interval does not remove uncertainty, and it does not by itself determine whether a result is important in a clinical or pharmacological sense. The primary endpoint information in the registry record does not include a confidence interval, so the precision of the bioavailability estimate cannot be evaluated.

Why does allocation matter?

The record calls the study non-randomized and states that the arms are not a like-for-like control comparison. General: Random allocation can help balance measured and unmeasured baseline characteristics across groups, while non-random allocation may leave group differences entangled with treatment differences. In a pharmacokinetic study, interpretation also depends on the precise route sequence, dose, timing, and analysis population. The record describes two cohorts and two periods, with a minimum washout interval, but does not fully specify the sequence of oral and IV treatment or participant-level assignment. Those details should not be inferred from the design label alone.

What do the sample-size illustrations represent?

General: A planning calculation asks how many participants might be needed under specified assumptions to detect a chosen effect with a chosen statistical power. It is not a count of observed participants with an outcome, and it is not evidence that a completed study had a particular probability of detecting its effect. The record characterizes its sample-size assumptions as a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It states that the effect to detect is a fraction of the observed effect. Such illustrations depend on those assumptions and should not be mistaken for the trial’s original design justification or an observed-power analysis. The protocol’s sample-size justification is not reported in the registry record.

The record lists 42 outcome measures and zero analyses. It does not provide enough information to reconstruct statistical models, standard-error calculations, confidence-interval methods, covariate adjustment, or testing procedures. General explanations of these methods cannot establish which procedures were used. For that reason, the endpoint definition and design labels support a description of the intended pharmacokinetic question, but not a reanalysis or a numerical conclusion.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 42 outcome measures, including the primary bioavailability outcome for dose level A and secondary outcomes for dose level B, other bioavailability summaries, maximum plasma concentrations, and times to maximum observed plasma concentration. When a study evaluates multiple outcomes, there can be multiple opportunities to observe a result that appears statistically notable by chance. General: multiplicity procedures can control or describe this concern by adjusting significance thresholds, organizing outcomes into a hierarchy, or distinguishing confirmatory from exploratory analyses.

The registry record does not report a multiplicity adjustment, testing hierarchy, or statistical analysis plan. It lists zero analyses, so no analysis results or multiplicity-adjusted findings are available in the record. It would be inappropriate to assume that tests were adjusted, unadjusted, or conducted in a particular sequence.

The record describes a Pharmacokinetic analysis population as participants who received at least one dose of balovaptan, with exclusions for significant violations of eligibility criteria, significant protocol deviations, or data-related reasons. The description ends before completing the data-related exclusion rule. The complete population definition, numbers excluded, and reasons for exclusion are not reported in the registry record. The handling of missing pharmacokinetic observations, including any imputation or participant-level rules, is also not reported in the registry record.

General: Missingness can affect an estimate if the availability of measurements is related to the values that would otherwise have been observed. The impact depends on why measurements are missing and how the analysis handles them. Without a complete population definition, missing-data approach, and outcome results, neither the extent nor the potential influence of missing data can be assessed. The registry record also does not describe interim analyses or a prespecified statistical plan.

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 four cohort-period groups: Cohort 1 Period 1, Cohort 1 Period 2, Cohort 2 Period 1, and Cohort 2 Period 2. In each group, eight participants are listed as at risk for serious adverse events, and zero are listed as affected by serious adverse events. Deaths are listed as zero in each group. No top serious adverse-event terms are listed.

The non-serious adverse-event figures are listed separately by group: four affected in Cohort 1 Period 1, six in Cohort 1 Period 2, five in Cohort 2 Period 1, and seven in Cohort 2 Period 2. These counts describe the registry’s period-specific entries. They should not be added or treated as a count of unique people, because the record does not explain whether participants contribute to more than one period’s figures.

General: Safety counts are descriptive. A zero count in the reported groups means that no affected participants were recorded for that event category in those entries; it does not prove that the event is impossible or that risk is absent. The record does not provide event-level detail for the non-serious events, severity, relationship to study drug, exposure-adjusted rates, or a formal comparison between treatments. The figures therefore support a limited description of reported counts, not a causal or comparative safety conclusion.

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

The study addresses a focused pharmacokinetic question: absolute oral bioavailability of balovaptan, with the primary endpoint defined for dose level A in Cohort 1. The registry record identifies oral and IV balovaptan as interventions and describes a completed Phase 1 study in healthy volunteers. It also names the endpoint’s unit and summary measures. These details clarify what the study was intended to measure.

What the record does not establish is the numerical answer. The primary endpoint estimate and its dispersion are not reported in the registry record, and no confidence interval or test result is available. Thus, the observed bioavailability cannot be described as high, low, precise, or uncertain on the basis of the endpoint entry alone. No result should be inferred from the study title, intervention names, or safety counts.

This is not a clinical efficacy trial as described in the record. Its listed primary outcome is pharmacokinetic, and the participants were healthy volunteers. The study therefore does not establish a clinical benefit, a treatment effect on a disease, or the balance of benefits and harms in a patient population. General: pharmacokinetic evidence can inform understanding of drug exposure, but exposure findings and clinical outcomes are different kinds of evidence.

The non-randomized design and the registry’s warning that the arms are not a like-for-like control comparison also constrain comparisons across groups. The available description does not specify the full treatment sequence or analysis details. The adverse-event entries can be stated as reported counts by cohort and period, but they do not establish that risks are equal or that a treatment caused or prevented an event.

The appropriate interpretation is therefore descriptive and limited: the registry records the design, population, endpoint definition, and safety counts, but not the numerical primary result or enough analysis detail to assess its precision. Conclusions beyond those recorded details are not supported by the registry entry.

13. Why This Trial Matters Statistically

This study is statistically useful as an example of how a pharmacokinetic question differs from a clinical-outcome comparison. Absolute bioavailability concerns exposure after oral administration relative to an IV reference. The endpoint is a percentage summarized by a geometric mean and geometric coefficient of variation, measures that are suited to describing positive, potentially multiplicative pharmacokinetic data.

The design details matter to interpretation. The study is non-randomized and open-label, and the registry explicitly cautions that its arms are not a like-for-like control comparison. It also describes two cohorts and two periods, with a minimum washout interval between the start days of the periods. Together, those features make it important not to treat cohort or period differences as a simple randomized treatment contrast. The detailed sequence and analysis procedures are not reported in the registry record.

The record also illustrates the distinction between describing an endpoint and reporting a result. It identifies what the primary endpoint measures and how it is summarized, but does not include the numerical estimate or its precision. Without those results, readers cannot assess the observed bioavailability or evaluate statistical uncertainty. Likewise, a planning illustration is not an observed power calculation or evidence of a treatment effect. General: planning assumptions describe a hypothetical design calculation; observed outcomes describe data collected in the study.

Finally, the safety entries are grouped by cohort and period. Such entries need to be interpreted at the level reported, rather than combined into a new total or assumed to represent separate participants. In this way, the trial highlights why design, endpoint definition, analysis transparency, and the distinction between planning and observed results are central to sound statistical interpretation.

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 primary limitation for interpreting the study’s main question is that the numerical bioavailability result is not reported in the registry record. The geometric mean and geometric coefficient of variation are identified, but their values are absent. No interval estimate or inferential result is reported, so the endpoint’s precision cannot be evaluated.

The design is non-randomized and open-label. The registry states that the arms are not a like-for-like control comparison, limiting any simple causal reading of differences between groups. The record does not fully describe how participants were assigned to treatment, the exact oral and IV administration sequence, or the participant-level analysis. The cohort descriptions specify dose levels and periods, but do not resolve those additional details.

The Pharmacokinetic analysis population description is incomplete: it begins by identifying participants who received at least one dose and exclusions for certain violations, deviations, or data-related reasons, but the final rule is truncated. The number and reasons for exclusions, missing-data handling, and analysis methods are not reported in the registry record. Nor does the record provide a statistical analysis plan, multiplicity procedures, or interim-analysis information.

The listed adverse-event information is presented by cohort and period and does not provide event-level details for non-serious events, severity, attribution, or exposure-adjusted comparisons. The entries should not be converted into totals or unique-participant counts. Finally, the study involved healthy volunteers and addresses pharmacokinetics; its findings, even if reported, would not by themselves establish clinical efficacy in a patient population.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study Investigating the Absolute Oral Bioavailability of Balovaptan After Single and Multiple Daily Oral Doses of Balovaptan in Healthy Volunteers — NCT03764449.
• Registry record last updated 2020-02-24; status last verified 2020-02.
• Results first posted 2020-02-24.
• 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

NCT03764449 is a completed Phase 1, single-center, non-randomized, open-label, parallel-group study of balovaptan in healthy volunteers. The registry lists an enrollment of 16, a start date of 2019-01-10, and a primary completion date of 2019-03-04. The study was conducted at one site in the Netherlands.

The primary endpoint is absolute oral bioavailability at dose level A in Cohort 1, expressed as a percentage and summarized by a geometric mean with geometric coefficient of variation. The record also lists secondary pharmacokinetic outcomes and safety counts by cohort and period. The numerical primary endpoint result, full statistical analysis details, and complete analysis-population description are not reported in the registry record.