Bioequivalence of a Fixed Dose Combination Tablet Containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl Compared to Two Film Coated Fixed Dose Combination Tablets RhinAdvil(R)(200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) Administered in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bioequivalence of a Fixed Dose Combination Tablet Containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl Compared to Two Film Coated Fixed Dose Combination Tablets RhinAdvil(R)(200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) Administered in Healthy Subjects (NCT02963701), a randomized phase 1 study. The primary outcome is Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Ibuprofen. (AUC0-tz).

2. Clinical Question

The study’s stated purpose was to assess bioequivalence, not to compare clinical benefit or symptom relief. Its summary identifies a secondary objective concerning the R- and S-ibuprofen enantiomers, and the registry lists further pharmacokinetic outcomes for ibuprofen and pseudoephedrine. The record does not report clinical efficacy outcomes. Interpretation therefore centers on the measured pharmacokinetic comparison and the precision of its estimate, rather than on a claim about clinical effects.

3. Trial Design

The registry classifies this as a completed, randomized Phase I trial in healthy volunteers, sponsored by Boehringer Ingelheim. It records enrollment of 56 and lists the start date as 2016-12-20 and primary completion date as 2017-01-31. The official title describes an open-label, randomized, laboratory-blind, single-dose, two-way crossover trial. In contrast, the registry’s model field is listed as parallel. This difference is an inconsistency in how the design is represented; the registry record does not explain it, so the design should not be reconstructed by choosing one description over the other.

The products were compared as fixed-dose combinations. The test product contained 400 mg ibuprofen and 60 mg pseudoephedrine-HCl in one tablet. The reference regimen consisted of two film-coated RhinAdvil® tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine-HCl per tablet. The primary objective in the summary was to demonstrate bioequivalence with respect to ibuprofen and pseudoephedrine. The stated secondary objective concerned R- and S-ibuprofen.

The reported primary analysis compares the Test Product (T) with the Reference Product (R) using an ANOVA and reports a T/R ratio. The primary endpoint is an area-under-the-curve measure of ibuprofen plasma concentration. The registry gives a detailed sampling schedule, from pre-dose through 30:00 hours post dose. It describes the primary analysis population as treated subjects with observations for both periods for at least one evaluable primary endpoint and without a major protocol deviation considered likely to interfere with absorption, distribution, metabolism, and excretion of the compound being measured.

The registry does not report the randomization sequence, allocation concealment, washout details, blinding procedures beyond the description in the official title, or the protocol’s sample-size justification. It also does not reconcile the crossover wording with the parallel model classification. These omissions limit what can be said about implementation and the design features that informed the 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.

Before assignment: This study was an Open-label, randomised, laboratory blind, single dose, two-way crossover, Phase I trial. A total of 56 healthy male and female subjects were randomised in the trial. Subjects were assigned randomly to one of two treatment sequences (Test-Reference, Reference-Test), before first drug administration.

Period 1 (Including Washout) (2 Days)

Reasons for not completing this period:

Period 2 (2 Days)

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Population (PK Set): All treated subjects that provided observations for both periods for at least one primary endpoint evaluable and without any major protocol deviation thought to interfere with the absorption, distribution, metabolism, and excretion of the compound to be measured were included in the PK population

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.

Population: Baseline characteristics were calculated on Safety Population. All subjects who received at least one dose of study medication were included in the safety population.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Ibuprofen. (AUC0-tz), measured over Samples were collected Pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 30:00 hours post dose..

The primary endpoint is the area under the plasma concentration-time curve for ibuprofen from time zero to the last quantifiable time point, designated AUC0-tz. It summarizes measured drug concentration over time up to the final sample at which the concentration can be quantified. The unit is hour nanogram per milliliter (h*ng/mL). Samples were collected pre-dose and at 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, and 30:00 hours post dose.

In general, an area-under-the-curve endpoint condenses concentration measurements across time into an exposure measure. It is useful in a bioequivalence comparison because it evaluates overall measured exposure rather than relying on a single concentration measurement. The endpoint does not, by itself, describe the timing of peak concentration or the peak concentration; those are distinct pharmacokinetic characteristics.

The registry reports geometric means and geometric coefficients of variation for the treatment groups, then presents an ANOVA-based T/R ratio and confidence interval. The geometric scale is commonly used for pharmacokinetic measures that are analyzed as ratios. The endpoint is not a direct measure of clinical response. The registry’s primary objective includes pseudoephedrine as an analyte as well, but the primary result described in the record concerns ibuprofen AUC0-tz.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports an ANOVA for the primary comparison, with the analysis parameter expressed as a T/R ratio in percent. ANOVA, or analysis of variance, is a modeling approach for comparing outcomes across groups or treatment conditions. In a pharmacokinetic bioequivalence analysis, the model is used to estimate the relative exposure of the test product compared with the reference product. The registry does not provide the model specification, covariates, sequence or period terms, transformation details, or diagnostic checks, so those features cannot be described from the record.

What does the ratio represent?

The T/R ratio expresses the estimated test-product exposure relative to the reference-product exposure. A ratio of 100% would indicate equal estimated exposure on this scale. The reported estimate is 99.16%. This is a point estimate: it gives the model’s central comparison, but does not express all uncertainty in the data. The registry reports a 90% confidence interval from 96.52% to 101.89%, which gives a range of estimates compatible with the analysis under its assumptions.

In general, a confidence interval is an uncertainty summary for an estimated quantity. Its interpretation depends on the study design, model, and assumptions; it does not mean that the true value has a particular probability of lying inside the interval after the data have been observed. For equivalence, the interval is typically compared with prespecified lower and upper limits. The registry record does not report those limits or an explicit equivalence conclusion.

Why use geometric summaries?

The endpoint values are reported as geometric means, accompanied by geometric coefficients of variation. Geometric summaries are often used for pharmacokinetic outcomes because exposure measures may be analyzed on a multiplicative or logarithmic scale, and the treatment comparison is naturally expressed as a ratio. The registry does not state the exact transformation used in the model, so this is general context rather than a description of undocumented analysis steps.

A coefficient of variation describes relative variability around a measure, rather than variability in the original unit alone. The reported geometric coefficients of variation are 23.66 for the reference and 19.3 for the test. Their interpretation depends on the calculation conventions used. The registry does not provide further detail about those conventions, so the values should be retained as reported rather than converted or reinterpreted.

What is the role of the analysis population?

The primary endpoint population is defined in the registry as treated subjects who provided observations for both periods for at least one evaluable primary endpoint and had no major protocol deviation thought to interfere with the measured compound’s absorption, distribution, metabolism, and excretion. The wording refers to both periods, consistent with the crossover description in the official title, while the model field says parallel. The record does not explain this discrepancy in design descriptions or give a separate analysis-population count beyond the arm counts shown for the primary endpoint.

Analysis populations affect which observations contribute to an estimate. In general, excluding observations can alter both the estimate and its precision, particularly if the reasons for exclusion are related to treatment or outcome. The record does not report participant-level exclusions, missing-data handling, or sensitivity analyses for the primary endpoint. It is therefore not possible to assess how robust the result was to alternative population definitions.

Why can over-dispersion matter?

In general, over-dispersion means that observed variability is greater than a model assumes. When a model underestimates variability, uncertainty intervals can become too narrow and tests can appear more decisive than the data justify. For a continuous pharmacokinetic endpoint analyzed with ANOVA, the key concern is whether the model represents the outcome distribution and design adequately. The registry does not report a dispersion diagnostic or a specific over-dispersion assessment, and no such finding should be inferred from the geometric coefficients of variation alone.

How should missing results and multiple outcomes be considered?

The record lists 13 outcome measures and 13 analyses, and identifies 9 secondary outcomes as posted. It also indicates that values are missing or not estimable for a two-arm comparison for another endpoint. That note does not identify the endpoint in the available record. The multiplicity strategy, if any, is not reported in the registry record. In general, when several outcomes are examined, multiplicity can increase the chance of at least one apparently unusual result if no adjustment or hierarchy is used. The degree of concern depends on the planned outcome structure and analysis plan, which are not described.

There is no reported p-value for the primary equivalence analysis. The available statistical evidence consists of the ANOVA-reported ratio and 90% confidence interval, alongside group geometric means and variability summaries. Interpretation should remain tied to those reported statistics and the missing information about the formal equivalence margins, model details, and handling of incomplete observations.

10. Analyses Reported by the Sponsor

The registry reports the primary comparison as an ANOVA estimate: a T/R ratio of 99.16%, with a 90% confidence interval from 96.52% to 101.89%. It does not separately identify a sponsor analysis and an independent recalculation in the record, nor does it give an alternative estimate for comparison. The analysis should therefore be read as the reported registry result, not as evidence of agreement or disagreement between two estimates.

The arm summaries list geometric means of 140500.0 for the reference product and 139300.0 for the test product, with geometric coefficients of variation of 23.66 and 19.3, respectively. These are descriptive summaries; the reported ratio and interval come from the ANOVA analysis and should not be replaced by an informal comparison of the arm summaries. No discrepancy between a sponsor result and recalculation is identified in the registry information.

The interval’s relevance to a formal bioequivalence conclusion depends on the acceptance limits specified in the analysis plan. Those limits and an explicit conclusion are not reported in the registry record. The ratio and confidence interval can be interpreted as the reported treatment comparison, while a claim that formal criteria were satisfied would require information not recorded.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 13 analyses, and reports that 9 secondary outcomes are posted. The primary objective refers to ibuprofen and pseudoephedrine, and the secondary objective concerns R- and S-ibuprofen. The listed secondary measures include AUC outcomes for ibuprofen and pseudoephedrine, as well as AUC and Cmax outcomes for the R- and S-ibuprofen enantiomers. The registry does not report a prespecified hierarchy among these outcomes or a multiplicity adjustment strategy.

In general, examining multiple outcomes can increase the chance of at least one result appearing notable by chance, especially when many comparisons are interpreted together. The importance of that issue depends on whether outcomes are confirmatory or exploratory, how they are ordered, and whether any adjustment was planned. The analysis plan is not reported in the registry record, so it is not possible to determine how multiplicity was handled or how secondary findings were intended to support the primary objective.

The registry notes that values are missing or not estimable for a two-arm comparison for another endpoint. The identity of that endpoint and the reason the values are unavailable are not reported in the registry record. Missing-data methods, imputation, sensitivity analyses, and participant-level reasons for unavailable results are also not reported. It is therefore not possible to judge whether missingness could affect the estimated treatment comparisons.

The primary endpoint population is defined using treated participants with observations for both periods for at least one evaluable primary endpoint and without major protocol deviations considered likely to interfere with pharmacokinetic measurement. The registry gives 55 per arm for the reported endpoint but does not report a detailed flow from enrollment to the analysis population, the exclusions made, or the number excluded for missing measurements. The relationship between this endpoint count and enrollment of 56 is not explained.

These gaps do not change the reported point estimate or interval, but they limit assessment of the full analysis strategy, completeness of outcome reporting, and robustness to missing observations or multiple testing.

12. 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.

The registry reports zero serious adverse events and zero deaths in both listed groups. It also reports zero affected for the other adverse-event category in each group. The counts at risk are 55 for Reference Product (R) and 56 for Test Product (T) in these safety listings. These group-specific figures should be read as recorded, and they are distinct from the endpoint-analysis counts reported for the pharmacokinetic comparison.

A zero count means that no event of the specified category was recorded in the listed group during the relevant reporting period. It does not establish that the risk of an event is absent. In general, safety summaries based on a limited number of observed participants have limited ability to characterize uncommon events, and a brief registry summary may not describe event definitions, surveillance methods, duration of follow-up, or attribution. Those details are not reported in the registry record.

The serious-event figures are descriptive and do not determine whether the products are bioequivalent. Conversely, the pharmacokinetic comparison does not establish comparative safety. The registry identifies healthy volunteers and a single-dose study in its official title, so these counts should not be extended to other populations or treatment settings. No further safety conclusion is warranted from the reported counts alone.

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

The result describes a pharmacokinetic comparison of ibuprofen exposure after a fixed-dose test tablet and the RhinAdvil® reference regimen. The reported T/R ratio for ibuprofen AUC0-tz is 99.16%, and the 90% confidence interval is 96.52% to 101.89%. These statistics indicate that the estimated relative exposure was close to equality, with uncertainty represented by the interval. The posted group geometric means and geometric coefficients of variation add descriptive context but do not replace the model-based estimate.

The result does not, on its own, demonstrate that formal bioequivalence criteria were met. That judgment requires the prespecified acceptance limits, which are not reported in the registry record. It also does not show whether pseudoephedrine met a corresponding criterion, because the described primary result is for ibuprofen AUC0-tz and the record does not supply a comparable usable result for every listed outcome.

The endpoint measures plasma exposure over time, not symptom relief, clinical benefit, or a patient-centered outcome. The registry describes healthy volunteers and a Phase I bioequivalence objective. The findings therefore should not be treated as an estimate of clinical effectiveness or as a comparison of outcomes in people being treated for a condition.

The result also does not establish that the products have identical pharmacokinetic profiles in every respect. AUC0-tz measures exposure through the last quantifiable time point; it is distinct from peak concentration and from other pharmacokinetic measures. The registry lists additional endpoints, but the multiplicity plan and some results are not reported in the registry record.

Finally, the recorded absence of serious adverse events and deaths is limited to the reported groups and period. It does not prove that uncommon harms cannot occur or characterize safety in settings beyond this trial. The most defensible reading is a precise description of the reported estimate and its interval, accompanied by recognition that the formal equivalence limits, detailed analysis plan, and several aspects of reporting are unavailable in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why a bioequivalence result is not read from the point estimate alone. The T/R ratio of 99.16% is close to 100%, but the interval from 96.52% to 101.89% is also needed to understand the uncertainty of the estimate. Formal interpretation depends on comparing that interval with prespecified acceptance limits. Without those limits in the registry record, the numerical result can be described but not classified as meeting or failing the planned criterion.

It also highlights the distinction between the estimand and the endpoint. The primary measure, ibuprofen AUC0-tz, represents plasma exposure over a defined part of the concentration-time profile. It is informative for a pharmacokinetic comparison, but does not directly answer questions about clinical outcomes. The registry’s stated aim and participant population make that distinction especially important.

The record also demonstrates the value of checking consistency across trial descriptions. The official title describes a two-way crossover, while the model field lists parallel. Since the record does not explain this difference, readers should recognize it as a reporting ambiguity rather than silently assume one design description is correct. Design details matter because they inform how treatment comparisons and their uncertainty are modeled.

Finally, the registry’s outcome counts, missing two-arm comparison note, and absent multiplicity and missing-data details illustrate how incomplete statistical reporting can limit interpretation even when a central estimate and confidence interval are available. Clear reporting of analysis populations, acceptance limits, model specification, and outcome handling is necessary to evaluate both the result and the strength of the evidence supporting it.

15. 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.

Several trial-specific limitations follow from what is and is not described in the registry. Most notably, the official title describes a two-way crossover design, while the model field classifies the trial as parallel. The record does not explain the discrepancy. Since the choice of design affects the interpretation and modeling of treatment comparisons, this ambiguity prevents a confident account of the implemented design beyond the descriptions as recorded.

The registry reports a T/R ratio and 90% confidence interval for the primary endpoint but does not report the prespecified bioequivalence acceptance limits or an explicit conclusion against those limits. The estimate can therefore be interpreted numerically, but the formal objective cannot be assessed from the result alone. The record also does not provide detailed ANOVA specification, model diagnostics, or a p-value.

Enrollment is listed as 56, while the reported primary endpoint analysis lists 55 in each product group. Safety counts are 55 for the reference and 56 for the test. The record does not explain these different counts or provide a participant flow, exclusions, or a detailed account of missing measurements. The analysis population is defined, but its exact membership and the reasons observations may not have contributed are not reported in the registry record.

The registry lists multiple outcomes and notes that a two-arm comparison is missing or not estimable for another endpoint. It does not identify that endpoint or describe how multiplicity was handled. Missing-data methods and sensitivity analyses are not reported. Finally, the study concerns healthy volunteers and the stated primary outcome is a pharmacokinetic measure; it does not provide evidence about clinical outcomes in patients. These limitations constrain conclusions to the reported exposure estimate and its uncertainty.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Bioequivalence of a Fixed Dose Combination Tablet Containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl Compared to Two Film Coated Fixed Dose Combination Tablets RhinAdvil(R)(200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) Administered in Healthy Subjects — NCT02963701.
• Registry record last updated 2018-09-27; status last verified 2018-01.
• Results first posted 2018-09-27.
• 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.

19. Record Summary

The registry describes a completed randomized Phase I trial in healthy volunteers, with enrollment of 56 and Boehringer Ingelheim as sponsor. Its official title characterizes the study as open-label, laboratory-blind, single-dose, and two-way crossover, while the model field lists parallel. This inconsistency is not explained in the registry record.

The primary endpoint is ibuprofen AUC0-tz. The reported ANOVA comparison gives a T/R ratio of 99.16% and a 90% confidence interval from 96.52% to 101.89%. The registry does not report the formal equivalence limits, so the result cannot be classified against those limits from the record alone. The listed serious adverse events and deaths are zero in both groups.

The registry also lists secondary pharmacokinetic outcomes, but multiplicity handling, missing-data methods, detailed model specification, and the explanation for varying analysis counts are not reported in the registry record. The findings support a description of the reported pharmacokinetic comparison, not a conclusion about clinical outcomes.