Three-way Crossover Study Comparing Ondansetron ODFS Administered With and Without Water to Zofran ODT Without Water: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Three-way Crossover Study Comparing Ondansetron ODFS Administered With and Without Water to Zofran ODT Without Water (NCT01220167), a randomized phase 1 study. The primary outcome is Cmax.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, three-way crossover study sponsored by Aquestive Therapeutics. Its official title describes a bioavailability comparison of ondansetron orally dissolving filmstrip with and without water against Zofran orally dissolving tablets without water. The registry status is completed. The study start and primary completion are both recorded as 2008-08.

The trial enrolled 18 healthy participants. Rather than assigning separate groups to receive only one treatment, the crossover design assigned participants to sequences in which each person received each of the three treatments. The registry describes Sequence ABC, Sequence BCA and Sequence CAB, with six subjects in each sequence. The treatment labels were A for ODFS without water, B for ODFS with water and C for Zofran ODT without water. One subject did not complete, according to the primary outcome population description.

A crossover design can make treatment comparisons more informative by allowing comparisons within the same participant, whose characteristics are then shared across treatment conditions. It also means that analysis should account for the repeated observations and sequence structure. These are general properties of crossover studies, not evidence about the analysis actually used in this trial.

The record does not report the length or details of treatment periods, washout intervals, the randomization procedure, or whether any protocol deviations occurred. It also does not report a masking procedure beyond identifying the study as open-label. Those details should not be inferred from the sequence descriptions.

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: Eighteen of 55 subjects were randomized. Of those not randomized, 29 did not meet eligibility criteria and 6 declined to participate. The 18 eligible participants reported to the study site on 22 Aug 2008, 25 Aug 2008 and 28 Aug 2008 for Period 1, Period 2, \& Period 3, respectively.

Period 1

Period 2

Period 3

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 18 subjects were enrolled. One subject did not complete.

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 Cmax, measured over 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose.

The listed primary endpoint is Cmax, measured in ng/mL and summarized as a mean with standard deviation. Cmax represents the maximum plasma concentration observed after dosing. Pharmacokinetic studies use this measure to characterize the peak concentration reached in blood, which can be compared across formulations or administration conditions as part of a bioavailability assessment.

The registry describes the endpoint as “Maximum Plasma Concentration (Time to reach maximum concentration).” These phrases refer to different concepts in standard pharmacokinetic terminology: Cmax is the concentration at the peak, while the time at which the peak occurs is generally described as time to maximum concentration. The endpoint title identifies Cmax, but the parenthetical wording introduces ambiguity about whether timing was also intended. The record does not clarify this wording.

Measurements were scheduled at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose. These are the stated assessment times, not reported Cmax results. The record gives no numerical means, standard deviations, participant-level observations, or treatment contrasts for Cmax. It therefore describes what was to be measured but does not show the magnitude or precision of any observed treatment difference.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with the distinction between the study design and the analysis results. The registry describes a randomized, open-label crossover study, but it does not report an analysis model or treatment-contrast results. The explanations below describe general statistical ideas relevant to this design; they should not be taken as a description of methods confirmed for this trial.

What does a crossover design contribute?

In a crossover study, participants receive more than one treatment according to an assigned sequence. Each participant can therefore contribute observations under multiple treatment conditions. General statistical analyses can compare outcomes within participants, which can account for stable participant characteristics that would otherwise contribute to between-person variation. This design can be efficient for outcomes that are measured repeatedly and are suitable for crossover comparisons.

Repeated treatment observations are not independent. A statistical model for a crossover study generally needs to account for the participant and the treatment sequence, as appropriate to the protocol and available data. The order of treatments can matter if there are period effects or carryover effects. A washout interval may be relevant to reducing carryover, but the washout details and the analysis approach are not reported in the registry record. It would therefore be inappropriate to assume that a particular model, period adjustment, or carryover assessment was used.

What do the listed summary statistics mean?

The primary outcome is specified as a mean with standard deviation. A mean describes the central average of a set of measurements. A standard deviation describes the spread of measurements around that average. These summaries can help readers understand both the typical level and variability of Cmax, but they do not by themselves quantify the uncertainty in a difference between treatments.

A confidence interval is a general way to express uncertainty around an estimated treatment contrast. It gives a range of values compatible with the data and the assumptions of the statistical method. A narrow interval indicates greater precision than a wide interval, while an interval spanning values in different directions may leave the direction of the contrast uncertain. No confidence interval for Cmax is reported in the registry record, so this kind of precision assessment cannot be made for the treatment comparisons.

A p-value, when reported, addresses how compatible the observed data are with a specified null hypothesis under the model assumptions. It is not a measure of the size or importance of an effect. The registry record does not report p-values or a statistical analysis for the primary outcome. Statistical significance therefore cannot be assessed from this record.

Why can pharmacokinetic outcomes need particular care?

Pharmacokinetic measurements such as plasma concentration can have distributions that are not well represented by a simple normal model. General analyses may use transformations or other approaches depending on the distribution and estimand. Whether this trial transformed Cmax, used a particular model, or assessed distributional assumptions is not reported in the registry record.

Concentration-time measurements can also be incomplete if participants miss visits or do not complete follow-up. The outcome description states that one subject did not complete, but does not say whether that subject's measurements were included, whether a Cmax could still be derived, or how incomplete data were handled. The registry record does not report a missing-data strategy or the number of observations contributing to each treatment summary.

When repeated measurements are correlated, treating each measurement as if it came from an unrelated participant can give an inappropriate estimate of uncertainty. General crossover analyses address this dependence through the analysis structure. The record's description of scheduled sampling times does not identify the method used to summarize the concentration profile or test treatment differences.

What can sample-size calculations tell readers?

A planning calculation can illustrate how many participants per arm might be needed under stated assumptions to detect a specified effect with a chosen significance level and power. Such an illustration depends on assumptions about variability, allocation, the target effect and the statistical model. It is a planning aid, not evidence that a study had a particular probability of finding a result after the data were collected. It should not be described as observed power.

The registry 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 between two arms and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. The record does not report the trial's own sample-size justification or a trial-specific statistical plan. Because the primary numerical effects and analysis results are not reported, the planning assumptions cannot substitute for interpretation of the actual comparisons. Any planning figures should be understood as illustrations under assumptions, not observed treatment effects or proof of adequate precision.

10. Multiplicity, Missing Data and Analysis Populations

The study compares three treatment conditions, so a complete analysis could involve more than one pairwise comparison. When multiple hypotheses are tested, the chance of at least one false-positive result can increase if no adjustment or testing strategy is specified. A study may address this with a prespecified primary contrast, a multiplicity adjustment, or a hierarchical testing plan. These are general options, not claims about the approach used in this trial.

The registry record does not report a statistical analysis plan, a prespecified contrast hierarchy, or a method for handling multiplicity. It lists three outcome measures and no analysis records, but does not identify which comparisons were intended to support the primary conclusion. Without those details and without reported results, the multiplicity approach cannot be evaluated.

Missing data also affect interpretation. The primary outcome description states that 18 subjects were enrolled and one subject did not complete. The record does not report why the subject did not complete, which treatment periods or measurements were affected, or whether the subject was included in any analysis. It does not identify an intention-to-treat, per-protocol, or pharmacokinetic analysis population. Those population definitions are not reported in the registry record.

For a crossover study, incomplete participation may leave some participants without observations under every treatment condition. General methods can use different approaches to available data, but their validity depends on assumptions about why data are missing and on the analysis model. The registry record does not state how missing observations were handled, whether sensitivity analyses were performed, or whether results differed across analysis populations. Consequently, neither the impact of the incomplete participation nor the robustness of any treatment comparison can be assessed.

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 lists safety information for the group titled “ODFS 8 mg With and Without Water and Zofran ODT Without Water.” It records 18 participants at risk for serious adverse events, zero affected by serious adverse events, 18 at risk for other adverse events, four affected by other adverse events, and zero deaths. These are the counts recorded for the group; they do not identify the specific events or their severity beyond the registry categories.

The record does not give descriptions of the four other adverse events, their timing, whether a participant experienced more than one event, or which treatment condition preceded an event. It also does not provide treatment-specific safety counts. The single grouped entry therefore cannot be used to compare safety across ODFS without water, ODFS with water, and Zofran ODT without water.

A zero count for recorded serious adverse events or deaths is a description of the registry entry, not evidence that every possible safety outcome was absent. The record does not report additional detail about ascertainment, duration of safety follow-up, or how events were classified. These limitations constrain interpretation of the safety figures.

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

The registry record shows that the trial was designed to compare the bioavailability of three ondansetron administration conditions in healthy adults. It identifies Cmax as the primary endpoint, specifies a mean and standard deviation summary, and lists post-dose sampling times. It also describes a randomized, open-label, three-way crossover design and records safety counts.

Those details do not reveal the observed Cmax under any treatment condition. The numerical endpoint summaries, treatment contrasts, confidence intervals and p-values are not reported in the registry record. As a result, readers cannot determine the direction or magnitude of any difference, its statistical uncertainty, or whether the conditions were similar according to a prespecified criterion. The record does not report an equivalence or non-inferiority margin, and no such conclusion should be inferred.

The study's stated aim included relative safety and tolerance, but the available safety entry is grouped across the treatments and does not describe the events. It cannot show whether one condition had more adverse events than another. The absence of recorded serious adverse events and deaths in the listed group should be interpreted as a count in the registry, not as a complete account of all safety evidence.

More broadly, a trial's design tells readers how the comparison was organized, while its results and analysis determine what conclusions the data can support. Here, the registry record is informative about the planned comparison and the endpoint, but not about the actual pharmacokinetic findings. Conclusions about comparative performance, precision, statistical significance, or clinical importance are therefore not supported by the information recorded.

The trial was conducted in healthy participants under fasting conditions. Its registry description does not establish how its findings would apply to other populations or circumstances, and, because numerical results are absent, it does not establish the findings even for the study population.

13. Why This Trial Matters Statistically

This study is statistically interesting because it uses a crossover design to compare formulation and administration conditions while holding each participant's stable characteristics constant across treatments. For pharmacokinetic outcomes, that structure can be useful: a participant's concentration measurements under different conditions can support within-person comparisons. In general, this can reduce some sources of variation compared with comparisons between unrelated groups.

The same structure requires careful analysis. Measurements from the same person are related, and treatment order or period may matter. An analysis must reflect the sequence and repeated observations, and its interpretation depends on protocol details such as timing and washout. The registry describes three treatment sequences but does not report the analysis model or the relevant period and washout details. This illustrates why design labels alone do not establish that an analysis has appropriately handled dependence and sequence.

The endpoint also highlights the importance of precise definitions. Cmax refers to peak concentration, while the endpoint description's parenthetical phrase refers to time to reach the peak. The distinction matters because concentration magnitude and timing answer different pharmacokinetic questions. The record's wording does not clarify whether the parenthetical phrase was intended as an explanation or as an additional measure.

Finally, this record demonstrates the gap between a stated research question and an interpretable result. It provides the treatment conditions, design and endpoint but not the numerical results or analysis. Without an estimate and its uncertainty, neither the size nor precision of a treatment contrast can be assessed. That limitation is central to statistical interpretation: a well-described comparison is not itself evidence about what the comparison found.

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 interpretation is that the registry record does not report numerical results for the primary Cmax endpoint. It gives no treatment-specific means or standard deviations, contrast estimates, confidence intervals, or p-values. The direction, magnitude and precision of the primary comparison therefore cannot be assessed.

The record lists three outcome measures but no analysis records. It does not identify the statistical model, the exact primary contrast, the analysis population, or any multiplicity strategy. It also does not report whether concentration data were transformed, how Cmax was derived from the sampling profile, or how incomplete profiles were treated. These omissions prevent evaluation of the analysis assumptions.

One subject did not complete, but the reason, timing and impact of this non-completion are not reported. The record does not say which treatment observations were available for that subject or whether the subject was included in an analysis. It also does not define the participant population used for the primary endpoint beyond the enrollment and non-completion statement.

The safety information is presented in a combined group rather than separately for each treatment condition. The record does not describe the four other adverse events or their relationship to treatment, and it does not give further context for the serious-event and death counts. This prevents treatment-level safety comparisons.

Additional design details—including washout intervals, treatment-period duration, randomization procedures and protocol deviations—are not reported in the registry record. The healthy-participant setting and fasting administration conditions also define the described study context; the record alone cannot establish applicability beyond it.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Three-way Crossover Study Comparing Ondansetron ODFS Administered With and Without Water to Zofran ODT Without Water — NCT01220167.
• Registry record last updated 2020-08-18; status last verified 2020-08.
• Results first posted 2020-08-18.
• 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

NCT01220167 is a completed Phase 1 randomized, open-label, three-way crossover study sponsored by Aquestive Therapeutics. It compared single doses of ondansetron 8 mg ODFS without water, ondansetron 8 mg ODFS with water, and Zofran ODT containing ondansetron 8 mg without water in healthy adults under fasting conditions.

The registry records 18 enrolled subjects, one subject who did not complete, and three treatment sequences with six subjects in each sequence. Cmax in ng/mL, summarized as a mean with standard deviation, is the listed primary endpoint. The record also provides a grouped safety entry with zero serious adverse events, four participants affected by other adverse events, and zero deaths.

Numerical Cmax results, treatment comparisons, analysis methods, and details of the other adverse events are not reported in the registry record. The record therefore describes the design and intended measurement but does not permit an assessment of comparative pharmacokinetic results.