Study to Investigate the Effect of Balovaptan on the QTC Interval in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Investigate the Effect of Balovaptan on the QTC Interval in Healthy Subjects (NCT03808298), a randomized phase 1 study. The primary outcome is Change-From-Baseline QTcF at Dose Level B Measured on 12-Lead ECGs Extracted From Continuous Recordings.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, double-blind, placebo-controlled, positive-controlled, single-center, multiple-dose crossover study in healthy subjects. The registry record describes a 3-period design with 12 treatment sequences. Enrollment was 57. The study is marked completed; its recorded start date was 2019-02-07 and its primary completion date was 2019-06-14.

Participants were assigned to sequences of treatments A, B, and either C or D. Treatment A was balovaptan at dose level A, described as the therapeutic dose; Treatment B was dose level B, described as the supra-therapeutic dose. Treatment C involved placebo for balovaptan and active control moxifloxacin 400 mg on Day 2. Treatment D involved placebo for balovaptan and moxifloxacin 400 mg on Day 15. Placebos for moxifloxacin were also listed for Treatments A and B. The registry record’s sequence descriptions vary the order of treatments across the 12 sequences.

In a crossover trial, participants receive more than one treatment condition in an assigned order. As a general statistical feature, this allows comparisons to use measurements from the same participant under different conditions, which can account for stable differences between participants. The order of treatment and changes over time can also matter in crossover studies. The registry record does not report the details of any analyses for period, sequence, or carryover effects.

The masking field is recorded as triple. The registry record does not specify which groups of people were masked. It also does not report the allocation procedure beyond randomized assignment, or the planned sample-size justification. Enrollment describes the recorded study enrollment; it does not, by itself, establish how many participants contributed data to each endpoint analysis.

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: QT/QTc population included all participants in the Safety population with ECG measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTcF value.

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 Change-From-Baseline QTcF at Dose Level B Measured on 12-Lead ECGs Extracted From Continuous Recordings, measured over Baseline (Predose Day 1), Day 14. (Each treatment period is 15 days.).

The primary endpoint was change from baseline in QTcF at balovaptan dose level B, measured using 12-lead ECGs extracted from continuous recordings. The specified comparison time was Day 14, with baseline defined as predose Day 1; each treatment period is described as 15 days. The endpoint was expressed as a least-squares mean, with a 90% confidence interval, in milliseconds.

QTcF is the corrected QT measure named in the registry record. The record does not state the correction formula, the ECG reading procedures, or the specific measurement time points within Day 14. The change-from-baseline format evaluates how the measurement during treatment differs from its baseline value. It does not, on its own, describe the absolute QTcF value or establish the clinical importance of a change.

ECG intervals are used to characterize electrical activity recorded at the heart. In this study, QTcF was the prespecified primary measure relevant to the stated investigation of balovaptan and the QTc interval. The registry record also lists secondary ECG outcomes, including QTcF at dose level A, heart rate, PR interval, QRS interval, and categorical outliers for QTcF, heart rate, and PR.

The numerical primary estimate, its confidence limits, and the endpoint analysis results are not reported in the registry record. Therefore, the direction, size, and precision of the primary endpoint result cannot be assessed from the registry information described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is described as a least-squares mean change from baseline in QTcF at dose level B. A least-squares mean is, in general, a model-based estimate of an average outcome for a specified treatment condition. Unlike a simple arithmetic average, it can reflect adjustments or structure included in the statistical model. The registry record does not identify the model terms, covariates, or estimation procedure, so the exact meaning of its adjustment cannot be reconstructed from the record.

What does change from baseline represent?

A change-from-baseline outcome compares a participant’s value during treatment with that participant’s baseline value. This can focus the analysis on within-participant change rather than on the treatment value alone. For a crossover study, the timing and definition of baseline matter because participants pass through multiple treatment periods. The record identifies baseline as predose Day 1 and specifies Day 14 for the dose level B primary measurement. It does not explain whether baseline was defined separately for each period or describe the detailed handling of repeated measurements.

Why use a crossover design?

In general, a crossover study assigns treatment conditions in a sequence so that participants receive different conditions over time. This can support comparisons within the same participant, reducing the influence of stable participant characteristics. However, measurements may also vary by period, and a previous treatment may affect measurements in a later period. The analysis therefore needs to account appropriately for the design. The registry record lists 12 sequences and a 3-period design, but does not report the statistical model or how period, sequence, or carryover were evaluated.

What does the confidence interval communicate?

The primary endpoint is paired with a 90% confidence interval. In general, a confidence interval expresses uncertainty around an estimated effect under the assumptions of the statistical method. The interval’s location indicates which effect values are compatible with the estimate and model; its width conveys precision. The registry record does not report the interval’s endpoints or the least-squares mean, so neither the estimated effect nor its precision can be described.

How should the analysis population be understood?

The registry record defines the QT/QTc population as participants in the Safety population who had baseline ECG measurements and at least one post-dose time point with a valid ΔQTcF value. This definition makes the availability of usable ECG data part of inclusion in the endpoint population. It does not state how many participants met that definition, how invalid measurements were identified, or how missing measurements were handled. The record also does not specify whether all randomized participants were included in any particular analysis.

What do the design and analysis counts tell a reader?

The registry record lists 29 outcome measures and 143 analyses. Such counts indicate that the record includes many outcome and analysis entries, but they do not explain which comparisons were prespecified as primary, how the analyses relate to each other, or whether any results were selected for emphasis. A multiplicity strategy is not reported. In general, when many outcomes or comparisons are tested, the chance of finding an apparently notable result by chance can increase unless the analysis plan addresses that issue. No adjustment method or hierarchy is specified in the registry record.

What is not available for independent interpretation?

The record does not report the primary endpoint estimate, its confidence limits, a p-value, or detailed model specifications. It also does not report a missing-data strategy, the number included in each endpoint analysis, or interim analyses. General statistical interpretation depends on these details because the estimate, uncertainty, population analyzed, and assumptions all contribute to what a result can support. Without them, the design can be described, but the primary effect cannot be independently assessed.

The study’s stated sample-size assumptions describe a planning illustration based on the observed effect: two-sided significance level 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. The record notes that time-to-event tables use total events and other tables use participants per arm. These are planning assumptions, not evidence of observed power or of the trial’s own sample-size justification. The registry record does not report that justification or numerical planning results for this study.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 29 outcome measures and 143 analyses. The primary outcome is described by multiple categories or time points and is not reduced in the record to a single comparison. The record does not identify a multiplicity procedure, a hierarchy among outcomes, or a family of comparisons to which an adjustment would apply. Thus, the extent to which the reported analyses were intended to support confirmatory conclusions is not reported in the registry record.

Missing-data methods are not reported in the registry record. The primary analysis population requires baseline ECG data and at least one valid post-dose ΔQTcF value. That definition explains an eligibility condition for the QT/QTc population, but does not describe how unavailable or invalid measurements were handled, whether any values were imputed, or how sensitivity to missing data was assessed. The number of participants in the primary analysis population is also not reported.

The record does not report an intention-to-treat, per-protocol, or other named analysis population for the primary endpoint. It defines the QT/QTc population in relation to the Safety population, but does not give the population counts or explain how deviations from assigned sequence were handled.

Interim analyses and stopping rules are not reported in the registry record. Nor does it report the detailed statistical model, any prespecified subgroup analyses, or how multiple time points were incorporated. These omissions limit evaluation of the analysis choices and the risk of selective emphasis across many outcomes and comparisons. They do not establish that a particular method was or was not used; the method is simply 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 record gives serious and other adverse-event counts by treatment group and for all participants. For Treatment A, 55 were at risk for serious events and 0 were affected; 55 were at risk for other adverse events and 11 were affected. For Treatment B, the corresponding counts were 52 at risk and 0 affected for serious events, and 52 at risk and 3 affected for other adverse events.

For Treatment C, 26 were at risk for serious events and 0 were affected; 26 were at risk for other adverse events and 6 were affected. For Treatment D, 26 were at risk for serious events and 0 were affected; 26 were at risk for other adverse events and 5 were affected. In the all-participants group, 57 were at risk for serious events and 0 were affected; 57 were at risk for other adverse events and 18 were affected. Deaths are recorded as 0 for each listed group, and no top serious-event terms are listed.

These are descriptive counts. Because this was a crossover study, group entries can reflect treatment-period exposure rather than mutually exclusive sets of participants; counts across groups should not be added or treated as independent. The registry record does not provide event definitions, exposure-adjusted rates, or detailed timing and attribution for these entries. The counts alone do not establish a causal relationship to a treatment.

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

This record describes a randomized crossover investigation of balovaptan’s effect on QTcF in healthy subjects, with placebo and moxifloxacin controls. It specifies a primary endpoint focused on change from baseline at balovaptan dose level B and names the measurement method, time point, summary measure, and confidence level. That information establishes what the study set out to measure and provides context for understanding the design.

However, the primary numerical result is not reported in the registry record. Without the least-squares mean and its 90% confidence interval, the observed change and its precision cannot be stated. The record also does not report the primary endpoint’s p-value or enough statistical detail to independently evaluate the analysis. Therefore, it cannot support a conclusion about whether the primary measure changed, the size of any change, or how uncertain an estimate might be.

The fact that the study was completed does not supply the missing endpoint result. Likewise, enrollment of 57 does not establish how many participants contributed to the primary analysis. The QT/QTc population definition requires available baseline and post-dose ECG information, but its size and missing-data handling are not reported.

The safety entries provide counts of serious and other adverse events by listed treatment group and for all participants. They are distinct from the primary ECG endpoint and do not resolve the missing efficacy or electrophysiology estimate. Their interpretation is also limited by the crossover structure and the absence of detail on event timing, attribution, and exposure-adjusted rates.

In general, a trial’s design and endpoint describe the question it was set up to investigate, while estimates and uncertainty are needed to interpret the observed data. The registry record supplies design details and outcome definitions, but the missing primary estimate prevents an assessment of the study’s observed QTcF finding. No treatment recommendation or conclusion about clinical effect follows from the recorded information alone.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of a crossover design applied to repeated ECG measurements. The randomized sequence structure and multiple treatment conditions make the design more complex than a simple comparison of two independent groups. In general, the appeal of a crossover comparison is that each participant can contribute measurements under different conditions, while the analysis must also account for the order and timing of those conditions.

The record distinguishes dose level A, dose level B, placebo conditions, and active control moxifloxacin given on Day 2 or Day 15. The primary endpoint focuses on dose level B, while secondary outcomes include QTcF at dose level A and other ECG measures. This illustrates why a clear endpoint hierarchy and transparent reporting of analysis methods matter when a trial includes numerous measures and repeated assessment times.

The record lists 29 outcome measures and 143 analyses, yet does not report the primary numerical estimate or a multiplicity strategy. From a statistical perspective, a large set of analyses makes it especially important to identify which result was primary, how uncertainty was quantified, and how results across outcomes and time points were interpreted. The missing estimates make it impossible to evaluate those issues against the observed findings.

The case also shows why enrollment and analysis population should not be treated as interchangeable. Although enrollment is 57, the primary endpoint population requires usable ECG information at baseline and after dosing. The number meeting that definition is not reported. Clear accounting of participants and missing measurements would help readers understand the reach of the estimate.

Finally, listing a confidence level without reporting the interval leaves the key measure of precision unavailable. The design can be described from the registry record, but statistical interpretation depends on the estimate, its uncertainty, and the analysis details that connect the data to the stated question.

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 consequential limitation in the registry record is the absence of the primary endpoint estimate and its 90% confidence interval. Without those results, the magnitude, direction, and precision of the specified change-from-baseline QTcF measure cannot be evaluated. A primary endpoint p-value is also not reported.

The record does not report the statistical model used for the crossover data, including how repeated measurements, treatment period, sequence, or possible carryover were addressed. The treatment sequence structure is described, but analytic handling of that structure is not. The correction formula for QTcF, ECG reading procedures, and detailed timing of measurements within the stated day are also not reported.

The primary population is defined by Safety population membership and availability of baseline and at least one valid post-dose ΔQTcF value, but the number analyzed is not reported. Missing-data methods, reasons for missing measurements, and sensitivity analyses are not reported in the registry record. Enrollment of 57 should therefore not be interpreted as the number contributing to the primary endpoint estimate.

The record lists many outcomes and analyses but does not report a multiplicity strategy or clearly explain how the analyses relate to a hierarchy of questions. It also does not report a sample-size justification for the trial. The stated planning illustration assumptions do not establish the design rationale or observed power for this study.

Safety reporting is limited to the listed counts. Detailed event descriptions, timing, attribution, and exposure-adjusted summaries are not reported. The crossover groups should not be understood as independent parallel arms. Together, these omissions restrict interpretation to the documented design and descriptive safety entries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Investigate the Effect of Balovaptan on the QTC Interval in Healthy Subjects — NCT03808298.
• Registry record last updated 2020-07-24; status last verified 2020-07.
• Results first posted 2020-07-24.
• 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

NCT03808298 is a completed Phase 1, randomized, triple-masked, single-center crossover study sponsored by Hoffmann-La Roche. The registry record reports enrollment of 57 healthy subjects, a start date of 2019-02-07, and a primary completion date of 2019-06-14. The study used a 3-period structure with 12 treatment sequences and included balovaptan, placebo, and active control moxifloxacin.

The primary endpoint was change from baseline in QTcF at balovaptan dose level B, measured on Day 14 using 12-lead ECGs extracted from continuous recordings. The record specifies a least-squares mean and 90% confidence interval but does not report the numerical endpoint result. It lists 29 outcome measures and 143 analyses; multiplicity and missing-data methods are not reported. Serious adverse events and deaths are recorded as 0 in each listed group, while other adverse-event counts are reported by treatment group and for all participants.