A Study to Investigate the Effect of Esomeprazole and the Effect of Food on the Pharmacokinetics of Balovaptan 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 Esomeprazole and the Effect of Food on the Pharmacokinetics of Balovaptan in Healthy Volunteers (NCT04156646), a randomized phase 1 study. The primary outcome is Maximum Plasma Concentration (Cmax) of Balovaptan.

2. Clinical Question

3. Trial Design

This was a Phase 1, single-center, open-label, randomized, part-randomized crossover study. It investigated the pharmacokinetics of a single dose of balovaptan under different food conditions and in the presence of esomeprazole. The registry records enrollment as 16 and status as completed. The study started on 2019-11-19, with primary completion on 2019-12-24.

A crossover design means participants can receive different study conditions in separate periods, so comparisons may be made within participants rather than only between separate groups. That structure can help account for stable differences between participants. The posted record describes treatment sequences ABC and BAC. In both, the fed and fasted balovaptan periods occur in a different order. The descriptions specify a 12 to 21 days wash-out between the first two periods. Period 3 includes esomeprazole administered once daily for 6 days; the available sequence descriptions end before fully detailing that period.

The registered treatment conditions are Balovaptan 20 mg Fed, Balovaptan 20 mg Fasted, and Balovaptan 20 mg Fasted + Esomeprazole 40 mg Fasted. The primary outcome record lists 16 for each condition. Those condition-level entries should not be added to infer a total number of distinct participants in a crossover study. The registry does not report the sequence assignment procedure in further detail, period-specific completion, or a statistical model for accounting for period and sequence effects.

Masking is listed as none, so the study was open-label. The registry identifies Hoffmann-La Roche as sponsor. Its study summary describes investigation of food and esomeprazole effects on balovaptan pharmacokinetics in healthy volunteers; the results should be interpreted as pharmacokinetic findings in that study population.

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.

Treatment Period 1 (6 Days)

Wash-out Period (12- to 21-days)

Treatment Period 2 (6 Days)

Wash-out Period (12- to 21-days)

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) of Balovaptan, measured over Samples at predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose.

The primary endpoint is maximum plasma concentration, or Cmax, of balovaptan, measured in ng/mL. It represents the highest observed concentration in plasma after dosing. The registry says Cmax was obtained directly from experimental data without interpolation and estimated using non-compartmental methods. Samples were scheduled at predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, and 192 hours post dose.

Pharmacokinetic endpoints describe drug exposure over time. Cmax focuses on the observed peak, rather than the total exposure over the full sampling period. It is useful for comparing concentration profiles across conditions, such as fed and fasted dosing or dosing with a concomitant medicine. The registry also lists secondary pharmacokinetic outcomes involving metabolites and esomeprazole, including peak concentrations and area-under-the-curve measures.

The posted primary results are geometric means, accompanied by geometric coefficients of variation. These summaries describe the central level and relative variability of Cmax on a multiplicative scale. They do not by themselves quantify the difference between conditions, establish a confidence interval, or provide a test of whether the conditions differ. The registry record does not report an adjusted or unadjusted primary comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is reported as a geometric mean with a geometric coefficient of variation. These are descriptive summaries, not a complete inferential analysis. The registry reports the values by treatment condition but does not provide a model-based contrast, confidence interval, or test result. The following statistical explanations are general and clarify what these summaries and missing analysis details mean.

Why use a geometric mean?

Pharmacokinetic measurements are often analyzed on a multiplicative scale because concentrations and exposure measures can be positively skewed. A geometric mean summarizes the central level after applying a logarithmic transformation and returning the result to the original scale. It is therefore not the same as an arithmetic average. For interpretation, it describes a typical concentration on a multiplicative scale rather than an average formed by adding all measured concentrations and dividing by the number of observations.

In a treatment comparison, analysts may compare log-transformed measurements and then express the contrast as a ratio after transforming back. That approach is general; the registry record does not say that this analysis was used for the posted Cmax results. No ratio or log-scale contrast is reported, so none can be inferred from the condition-specific geometric means alone.

What does the geometric coefficient of variation describe?

A coefficient of variation expresses dispersion relative to the scale of the measurements. The geometric version is associated with variation on a logarithmic scale. It helps describe how broadly measurements are distributed around a geometric mean, while avoiding the units of the outcome itself. Here, the registry reports a geometric coefficient of variation for each condition. These values do not supply the individual observations, the correlation between a participant’s measurements in different periods, or the uncertainty of a treatment contrast.

Dispersion and uncertainty are related but different ideas. Dispersion describes variation among measurements. Uncertainty in an estimated treatment effect depends on the design, the analysis, the sample information, and the contrast being estimated. A coefficient of variation is not a confidence interval and should not be interpreted as one.

Why is a confidence interval useful?

In general, a confidence interval presents a range of effect estimates compatible with the data and the assumptions of the analysis. It communicates precision: a narrower interval indicates more precise estimation than a wider interval, while the interval’s location describes which effect values remain compatible with the analysis. A point estimate without an interval can show direction or relative magnitude only when a contrast is explicitly defined; it does not show how uncertain that estimate is. The registry record does not report confidence intervals for the primary endpoint.

How does crossover structure affect analysis?

In general, crossover studies collect measurements under different conditions from the same participants. A within-participant comparison can control for stable characteristics that would otherwise contribute to variation between people. Statistical analysis should respect that pairing, because measurements from the same participant are related rather than independent. A model may also need to account for period or sequence effects, depending on the design and analysis plan. The registry record describes treatment sequences and periods but does not report the primary analysis model, how pairing was handled, or whether period and sequence effects were assessed.

Wash-out intervals are intended in general to reduce carryover from an earlier treatment period into a later one. The sequence description gives a 12 to 21 days wash-out between the first two periods. The registry record does not report how wash-out adequacy was evaluated or how possible carryover was addressed analytically. No conclusion about those checks can be drawn from the descriptive outcome values.

What does the sampling schedule contribute?

Cmax is the highest measured concentration, so its value depends in part on when samples are collected. The registry lists predose sampling and repeated post-dose measurements through 192 hours. The endpoint description says the peak is taken directly from observed measurements without interpolation. In general, observed-peak methods do not estimate a concentration between scheduled samples. A peak occurring between sample times may therefore not be captured exactly, although the record does not quantify any such effect for this study.

The endpoint was estimated using non-compartmental methods. In general, these methods summarize pharmacokinetic measurements without requiring a specified compartment model to describe the body’s handling of a drug. That description identifies the broad method family but does not provide details such as software, calculation conventions, or handling of values below assay limits. Those details are not reported in the registry record.

How should planning illustrations be understood?

In general, a sample-size planning illustration asks how many participants per arm might be needed under specified assumptions to detect a chosen effect with a chosen significance level and power. Such an illustration is prospective planning, not a measure of the study’s observed power. The registry notes that its planning assumptions use the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. It also states that the target effect is a stated fraction of the observed effect. Those assumptions do not establish that the trial itself used them to select its enrollment.

The registry record does not report the trial’s sample-size justification or protocol-level statistical plan. Planning illustrations based on observed effects should be treated cautiously because an effect estimated from a small study can be unstable. They do not replace confidence intervals or an analysis of the data from the crossover design. No new sample-size estimates or power calculations can be derived from the posted summaries alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 43 outcome measures and reports 30 secondary outcomes as posted. The secondary outcomes include peak plasma concentrations and area-under-the-curve measures for M2 metabolite, M3 metabolite, and esomeprazole. The primary outcome is balovaptan Cmax. The number of outcome measures and the number of posted secondary outcomes do not tell how many statistical tests were performed or how those tests were handled.

Multiplicity arises when several outcomes or comparisons are tested. In general, repeated testing can increase the chance of obtaining an apparently notable result by chance if no adjustment or hierarchy is used. A statistical plan may define a primary comparison, testing order, or adjustment method. The registry record does not report a multiplicity strategy, a hierarchy among the secondary outcomes, or a protocol-level analysis plan. The outcome analysis record lists zero analyses, so formal tests and their results are not posted there.

Missing-data handling and analysis populations also matter. The primary outcome’s population field is blank. The registry does not report a definition of the analysis population, exclusions from analysis, missing concentration-data methods, or how incomplete periods were handled. It does not report whether all participants completed each condition or whether any measurements were excluded. The condition-level outcome entries list 16 for each condition, but that does not supply these missing methodological details.

These gaps limit interpretation of precision and robustness. The geometric means and coefficients of variation can be described as posted, but the registry record does not allow confirmation of the planned inferential approach or assessment of how missing observations and multiple outcomes affected conclusions.

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 reports serious adverse events by treatment condition. For Balovaptan 20 mg Fed, 0 serious adverse events were recorded among 16 at risk. For Balovaptan 20 mg Fasted, 0 were recorded among 16 at risk. For Balovaptan 20 mg Fasted + Esomeprazole 40 mg Fasted, 0 were recorded among 16 at risk. The record also reports 0 deaths in each condition.

The adverse event entries list other adverse events affecting 1 in each condition, with 16 at risk in each. These are recorded separately from serious adverse events. The registry’s list of top serious adverse event terms is empty, consistent with the absence of serious events reported in these entries; it does not provide further event descriptions for the other adverse events.

These figures are descriptive safety counts for the study conditions. They do not establish that an event could not occur, nor do they quantify comparative safety with precision. The record does not report event definitions beyond the serious and other categories in the posted results, timing, severity details for the other events, or whether the same participant contributed an event in more than one crossover period. Because the study is small and each condition has limited exposure information in the registry, the counts should be read as a report of what was recorded, not as a broad estimate of risk.

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

The posted primary outcome describes the peak balovaptan concentration observed under three conditions in healthy volunteers. The geometric mean Cmax values are 74.83 ng/mL after fed dosing, 97.44 ng/mL after fasted dosing, and 79.67 ng/mL after fasted dosing with esomeprazole. Their corresponding geometric coefficients of variation are 42.6%, 44.6%, and 38.3%. These numbers summarize central levels and relative variability for the recorded conditions.

The results do not report a treatment contrast, confidence interval, or statistical test. Therefore, the posted point estimates do not establish how large a food-associated or esomeprazole-associated change is, how precise such a change would be, or whether a formal comparison supports a difference. The ordering of the geometric means is descriptive and should not be converted into a claim about the strength or certainty of an effect.

The endpoint is a pharmacokinetic measure, not a measure of clinical response. The trial studied healthy volunteers and a single dose of balovaptan under specified conditions. It does not, from the posted primary outcome alone, address longer-term use, clinical outcomes, or response in people with Autism Spectrum Disorder. The condition listing does not change the population described in the study summary.

Likewise, the safety entries report no serious adverse events or deaths in the listed conditions and report other adverse events affecting 1 in each. These observations are limited to the recorded study experience and do not determine the likelihood of uncommon or later events. A fuller assessment would require additional evidence and analysis that the registry record does not report.

The most defensible reading is therefore narrow: the record provides descriptive Cmax summaries and adverse event counts for a completed crossover pharmacokinetic study. It does not provide enough inferential detail to judge the precision of condition differences or to make broad claims about clinical effects.

13. Why This Trial Matters Statistically

This trial is statistically useful as an example of a pharmacokinetic crossover design. Each participant may contribute measurements under multiple conditions, which can make within-participant comparisons informative when the analysis preserves the paired structure. At the same time, condition-level summaries alone do not show the paired response pattern that a crossover analysis relies on.

The study also illustrates why the endpoint scale and summary matter. Cmax is an observed peak concentration, and the results are reported as geometric means with geometric coefficients of variation. Those summaries fit a common way of describing positively skewed pharmacokinetic measures, but they do not substitute for an explicit treatment contrast and its uncertainty. A reader can describe the posted values while recognizing that the inferential question remains unanswered in the registry results.

The sampling schedule is another statistical consideration. The peak is defined from observed measurements without interpolation, so its estimation depends on the timing of samples. Dense sampling can help characterize concentration profiles, but no sampling schedule eliminates all uncertainty about a peak between measurements. The registry reports the schedule but not an assessment of its impact on the endpoint.

Finally, the record distinguishes descriptive results from analysis reporting. It contains primary outcome summaries and secondary outcome listings, but the analysis record lists zero analyses. That distinction matters: outcome values can be posted without the contrasts, uncertainty measures, modeling decisions, or multiplicity approach needed for a full inferential account. The study therefore offers useful design and measurement details while leaving important analytical questions not reported in the registry record.

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 main limitation for interpretation is the absence of a posted comparative analysis for the primary endpoint. The registry reports condition-specific geometric means and geometric coefficients of variation, but no contrast estimate, confidence interval, or inferential test. The analysis record lists zero analyses. This prevents assessment of the precision of any food or esomeprazole comparison from the registry results.

The crossover structure makes participant-level pairing and period handling important, yet the statistical model and analysis population are not reported in the registry record. The sequence descriptions identify treatment order and a wash-out interval between the first two periods, but the available descriptions are truncated before fully detailing the final period. The record does not state how possible period, sequence, or carryover effects were evaluated.

The primary outcome population field is blank, and missing-data methods, completion by period, and rules for excluding measurements are not reported in the registry record. The result summaries do not include individual observations or a description of the within-participant relationships across conditions. This limits evaluation of variability and robustness beyond the reported geometric coefficients of variation.

The study enrolled healthy volunteers and examined a single-dose pharmacokinetic endpoint. These features constrain generalization to other populations, longer exposure, and clinical outcomes. The registry condition listing includes Autism Spectrum Disorder, but the study description identifies healthy volunteers. The record also does not report the trial’s sample-size justification, protocol statistical plan, or multiplicity approach. These omissions should be kept distinct from the descriptive outcome values, which remain the results posted for the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Investigate the Effect of Esomeprazole and the Effect of Food on the Pharmacokinetics of Balovaptan in Healthy Volunteers — NCT04156646.
• Registry record last updated 2021-03-16; status last verified 2021-02.
• Results first posted 2021-03-16.
• 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

NCT04156646 is a completed Phase 1, single-center, open-label crossover study sponsored by Hoffmann-La Roche. The registry records enrollment as 16 and describes the study population as healthy volunteers. It investigated balovaptan pharmacokinetics under fed, fasted, and fasted-plus-esomeprazole conditions.

The primary endpoint was balovaptan maximum plasma concentration. Posted geometric mean values were 74.83 ng/mL for the fed condition, 97.44 ng/mL for the fasted condition, and 79.67 ng/mL for the fasted condition with esomeprazole. The registry also reports geometric coefficients of variation of 42.6%, 44.6%, and 38.3%, respectively. No comparative estimate, confidence interval, or formal analysis is posted for the primary outcome.

The record reports 0 serious adverse events and 0 deaths in each condition, with other adverse events affecting 1 in each. Secondary pharmacokinetic outcomes are listed, but multiplicity procedures, missing-data handling, analysis populations, and the statistical plan are not reported in the registry record.