To Determine Blood Concentrations of Ibuprofen and Caffeine in a Tablet Against Ibuprofen Alone From Another Tablet: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Determine Blood Concentrations of Ibuprofen and Caffeine in a Tablet Against Ibuprofen Alone From Another Tablet (NCT02629354), a randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of S-ibuprofen.

2. Clinical Question

The question is pharmacokinetic: it concerns the concentration of one ibuprofen enantiomer measured in plasma, rather than symptom relief or another clinical outcome. The trial also lists secondary pharmacokinetic outcomes involving area under the plasma concentration-time curve for S-ibuprofen, R-ibuprofen, and ibuprofen. The posted primary result is a relative comparison of geometric means, not a comparison of arithmetic means or a measure of clinical benefit.

The interval communicates uncertainty around the estimated relative concentration. It extends on both sides of the reported ratio, so the point estimate should not be read as an exact or certain difference between products. The registry record does not report an equivalence margin or a prespecified range of acceptable ratios. The result therefore describes the estimated comparison and its precision, but does not by itself establish whether the products meet a particular equivalence criterion.

3. Trial Design

This was a Phase 1, randomized, open-label, single-center study with a single dose, two periods, and two sequences. Its crossover model means participants received treatments across study periods rather than being assigned only to a parallel treatment group. The registry identifies the combination tablet as the test product and the ibuprofen-only tablet as the reference product. Both were studied under fed conditions.

The trial title describes evaluation of relative bioavailability in at least 30 healthy males and females. The registry reports enrollment of 36 and a completed status. The recorded study start is 2015-11 and the primary completion is 2016-01. The registry does not report the treatment sequence details, the interval between periods, or whether any participants did not complete both periods.

The primary pharmacokinetic population is defined as participants who completed PK sampling in both periods and had no major protocol deviations considered to affect analysis of the PK data. The posted arm summaries each report n=26. In a crossover study, treatment-specific summaries can reflect observations from the same participants across periods; the registry’s arm counts should not be interpreted as evidence of separate, independent groups. The registry record does not provide a participant flow account that reconciles enrollment with the primary analysis population.

Randomization and the crossover structure are relevant to how treatment comparisons are made, while open-label status means masking was absent. The registry does not report the randomization procedure, sequence allocation details, or measures used to manage possible period or sequence effects. It also does not report a detailed protocol or statistical analysis plan. Those omissions limit what can be said about the implementation of the design beyond the characteristics explicitly recorded.

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: All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist site ensured that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

Period 1

Washout Period

Period 2

Follow-up

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population: all subjects who completed the PK sampling in both periods and with no major protocol deviations considered to impact on the analysis of the PK data were included.

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: Randomized population: all subjects randomized to a treatment sequence.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of S-ibuprofen, measured over Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose.

The primary endpoint is maximum observed plasma concentration, or Cmax, of S-ibuprofen. It is the highest concentration of S-ibuprofen recorded directly from the plasma concentration-time data after dosing. The registry reports the unit as nanogram (ng)/ millilitre (mL) and summarizes the endpoint using a geometric mean with geometric coefficient of variation as the measure of dispersion.

Concentration measurements were scheduled within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose. Cmax captures the observed peak in the sampled concentration profile. It is one aspect of drug exposure: it does not, on its own, describe the full concentration-time profile or the total area under that profile.

In general, pharmacokinetic endpoints are used to characterize drug exposure and compare how exposure differs between formulations or treatments. The registry’s stated endpoint is specifically an observed peak, not a clinical symptom or safety outcome. Its value depends on the measured samples and the timing of those samples; the record does not report additional details about concentration modeling or handling of measurements between scheduled times.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

In general, a crossover trial compares treatments received by participants in different study periods. Each participant can contribute information under more than one treatment, allowing a within-participant comparison. This can reduce the influence of stable differences between participants, but the design also makes period, sequence, and possible carryover considerations relevant. The registry identifies a randomized, two-period, two-sequence crossover design, but does not report the analysis model details or the interval between periods.

What does the geometric mean represent?

The endpoint is summarized by geometric means. In general, a geometric mean is useful for measurements that are positive and can have a right-skewed distribution. It is based on values on a logarithmic scale and then expressed back on the original measurement scale. A ratio of geometric means is consequently a natural way to describe relative exposure. The reported test-to-reference percent ratio of 113.77 is the relative estimate from the registry’s ANOVA analysis.

The geometric coefficient of variation describes dispersion on a relative scale, rather than giving the distance of observations from the mean in the same way as a standard deviation. The registry reports values of 38.0 for the reference product and 34.9 for the test product. These figures indicate variability in the measured endpoint, but they do not show the distribution of individual observations or the uncertainty of the treatment ratio. The confidence interval addresses uncertainty in the estimated comparison; the coefficient of variation describes variability in the data.

How should the confidence interval be read?

In general, a confidence interval is a range generated by a statistical procedure to express uncertainty about an estimated quantity. It is not a range containing a stated proportion of individual participants’ measurements, and it does not mean that every value inside it is equally likely. The registry reports a 90% confidence interval from 98.99 to 130.75 for the test-to-reference ratio. The interval’s width is relevant to precision: a broader interval leaves greater uncertainty about the size of the relative difference.

A confidence interval must be interpreted in the context of the question and decision rule. For bioequivalence assessment, the conclusion depends on the prespecified acceptance limits and the appropriate analysis plan. Those limits and a decision rule are not reported in the registry record. The numerical interval alone therefore cannot establish whether a formal criterion was satisfied.

What does ANOVA contribute?

The registry identifies ANOVA as the method for the reported comparison. In general, analysis of variance is a framework for comparing means or model-based treatment effects while accounting for terms specified in the model. For a crossover analysis, the chosen model can be important because observations are collected across periods and treatments. The registry does not report which terms were included, whether concentrations were transformed before analysis, or how the crossover structure was represented. Those details should not be inferred from the method label alone.

The ratio reported by the ANOVA analysis is the sponsor-reported comparison in the registry. The arm summaries provide context for the endpoint, but an independent calculation from group summaries would not necessarily reproduce a crossover model estimate. The record does not provide the individual-level data or enough model specifications to recreate the sponsor analysis.

Why does the sampling schedule matter?

Cmax is obtained from the observed concentration-time data. Its estimate depends on the concentration measurements collected and the sampling schedule. The registry lists measurements before dosing and at multiple post-dose times through 24 hours. In general, denser sampling around the time of a peak can help characterize the observed maximum, whereas a schedule that misses a peak may capture a lower sampled value. The record does not state how the peak’s timing was handled beyond defining Cmax as the maximum observed concentration.

The endpoint is distinct from area under the curve, which summarizes exposure across time. The listed secondary outcomes include AUC0-INF for S-ibuprofen, R-ibuprofen, and ibuprofen. In general, Cmax and area-under-the-curve measures answer related but different pharmacokinetic questions: a peak concentration is not interchangeable with total exposure. No numerical secondary results are reported in the registry record.

Finally, the analysis population is defined by completion of PK sampling in both periods and the absence of major protocol deviations considered to affect PK analysis. In general, restricting an analysis population can affect how broadly results apply, and decisions about protocol deviations can influence which observations are included. The registry does not provide a list of exclusions or details on how missing measurements were handled.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s ANOVA analysis as a test-to-reference percent ratio of 113.77, with a 90% confidence interval from 98.99 to 130.75. The analysis is identified as a comparison of the test product with the reference product. No p-value is reported for this result.

A separate recalculated estimate is not reported in the registry record. The arm summaries provide geometric means and geometric coefficients of variation, but they do not include enough information to reconstruct the crossover ANOVA result. In particular, the record does not provide individual observations or the full model specification. A calculation based only on summary values would not necessarily account for the design and analysis used by the sponsor.

The registry does not flag a discrepancy between the posted analysis and a recalculation. The sponsor’s reported analysis is therefore the relevant result for describing the study’s stated comparison. The absence of a discrepancy flag does not supply missing model details, nor does it establish an equivalence conclusion: the acceptance limits and decision rule are not reported in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures and nine analyses. It names secondary pharmacokinetic outcomes for area under the plasma concentration curve of S-ibuprofen, R-ibuprofen, and ibuprofen. The primary endpoint is maximum observed plasma concentration of S-ibuprofen. The registry entries do not provide numerical results for the listed secondary outcomes.

When a study assesses multiple outcomes or performs multiple statistical comparisons, the chance of at least one apparently unusual result can increase. In general, a multiplicity strategy may control that risk or distinguish a prespecified primary analysis from exploratory analyses. The registry record does not report whether any adjustment for multiple comparisons was planned or applied, how outcome families were defined, or whether any analyses were designated exploratory. No multiplicity-adjusted inference should be assumed.

The primary PK population included participants who completed sampling in both periods and had no major protocol deviations considered to affect the analysis. Posted arm summaries report n=26 for each product. The registry reports enrollment of 36, but it does not give a participant flow account explaining the difference between enrollment and the primary population counts. It does not state whether incomplete sampling, protocol deviations, or other reasons account for participants not represented in the PK summaries.

Missing-data methods are not reported in the registry record. The record does not describe whether measurements were missing, how any missing observations were handled, or whether sensitivity analyses assessed the impact of missing data. It also does not report a broader intention-to-treat analysis population or a separate per-protocol definition beyond the stated PK-population criteria.

The record’s omissions matter because exclusions and missing measurements can affect the population represented by the estimate. The posted ratio should be understood as the result for the stated PK population and analysis, with uncertainty about the handling of unreported missingness and multiplicity.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

For the reference product, the registry reports 0 serious adverse events among 36 at risk and 0 other adverse events among 36 at risk. For the test product, it likewise reports 0 serious adverse events among 36 at risk and 0 other adverse events among 36 at risk. The deaths field is not populated for either group; deaths are therefore not reported in the registry record, rather than documented as zero.

These figures are counts recorded in the registry’s adverse-event summary. They do not show event timing, severity categories beyond the serious-event distinction, or whether events were judged related to treatment. The record does not provide further adverse-event terms in the listed serious-event summary.

In general, the absence of reported events in a study does not establish that an event cannot occur. Safety interpretation depends on the population observed, the observation period, event definitions, and completeness of reporting. The study involved a healthy population and a single-dose design; its adverse-event summary should not be treated as a broad safety assessment across other populations or dosing circumstances.

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

The result describes the relative maximum observed plasma concentration of S-ibuprofen after the combination tablet compared with the ibuprofen-only tablet, in healthy participants under fed conditions. The reported test-to-reference percent ratio is 113.77, and its 90% confidence interval is 98.99 to 130.75. The posted arm summaries report geometric mean Cmax values of 13270.0 for the reference product and 14970.0 for the test product.

These statistics do not establish a clinical benefit or a lack of benefit. Cmax is a pharmacokinetic measure, not a measure of pain relief or another patient-centered outcome. It also does not summarize total drug exposure; the registry lists area-under-the-curve measures separately. No numerical result for those secondary measures is reported in the registry record.

The result does not establish that the products are equivalent under a formal bioequivalence standard. Such an interpretation requires prespecified acceptance limits and an analysis decision rule, which are not reported in the registry record. The confidence interval conveys uncertainty around the estimated ratio, but the interval alone cannot replace those criteria.

The result also does not describe concentrations in populations beyond the healthy male and female participants studied, or under conditions other than the fed, single-dose design. It does not provide a basis for inferring outcomes from repeated dosing or for judging individual responses. The registry’s open-label status, the limited detail about the ANOVA model, and the absence of a participant flow account further constrain interpretation.

In short, the posted result is a study-specific estimate of relative S-ibuprofen peak exposure, with a reported confidence interval. Its meaning is limited to that endpoint, analysis population, and study setting; broader clinical and equivalence claims require information not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates how a pharmacokinetic question can be framed as a comparison of geometric means and a ratio. The endpoint is a measured plasma concentration, and the posted analysis reports a test-to-reference estimate with a confidence interval. Those quantities describe both the direction and precision of a relative exposure estimate, while remaining distinct from clinical outcomes.

The crossover design also illustrates why the analysis method matters. Participants contribute observations across treatment periods, so the treatment comparison is not necessarily recoverable from arm summaries alone. A reported ANOVA result can depend on how the design is represented in the model. Because the registry gives the method label but not the model specification, the report is informative about the intended comparison but does not allow full independent reconstruction.

The distinction between the point estimate and its interval is important. The ratio is a single estimate, whereas the interval expresses uncertainty under the reported analysis. Formal interpretation against an equivalence standard would additionally require an acceptance range and a prespecified decision rule. Those are not reported, so the statistical result should be described without making a stronger classification.

The record also shows why analysis populations and reporting completeness matter. It defines a PK population based on completion in both periods and protocol-deviation criteria, but provides no participant flow account or missing-data methods. The safety summary records no adverse events in the reported categories, but does not give details that would support a broad safety conclusion.

These features make the trial useful for teaching the relationship among design, endpoint, model, uncertainty, and interpretation. They also demonstrate the limits of registry summaries: a numerical estimate can be clearly reported while important details needed for independent evaluation remain unreported.

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.

The registry provides limited detail about the crossover implementation. It identifies randomization, two periods, and two sequences, but does not report the sequence-generation method, allocation procedures, or interval between periods. It does not describe possible period or carryover considerations or how the ANOVA model addressed them.

The primary analysis population is defined by completed PK sampling in both periods and no major protocol deviations considered to affect PK analysis. The posted arm summaries report n=26 for each product, while enrollment is 36. A participant disposition or exclusion breakdown is not reported in the registry record, so the reasons that observations are absent from the summaries cannot be assessed.

The record does not provide individual-level concentration data, the complete analysis specification, or a detailed protocol. As a result, the reported ANOVA estimate cannot be independently reproduced from the recorded summary statistics alone. The handling of missing measurements, outliers, and protocol deviations is not reported. Nor does the record state whether multiplicity adjustments or sensitivity analyses were used.

Interpretation is also constrained by the absence of an equivalence margin and decision rule. The ratio and confidence interval can be described, but the registry does not state the criteria by which the comparison would be judged against a formal bioequivalence standard. Numerical results for the listed secondary outcomes are not included in the registry record.

Finally, the trial concerns a single dose under fed conditions in healthy participants and is open-label. The results therefore describe that study setting and endpoint. The registry record does not establish how findings extend to other populations, dosing conditions, or clinical outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: To Determine Blood Concentrations of Ibuprofen and Caffeine in a Tablet Against Ibuprofen Alone From Another Tablet — NCT02629354.
• Registry record last updated 2017-05-05; status last verified 2017-03.
• Results first posted 2017-03-16.
• 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.

19. Record Summary

NCT02629354 is a completed Phase 1, randomized, open-label, single-center, two-period, two-sequence crossover study. It compared a fixed-dose tablet containing ibuprofen 400 mg and caffeine 100 mg with a tablet containing ibuprofen 400 mg alone under fed conditions. The registry reports enrollment of 36, a study start of 2015-11, and primary completion in 2016-01.

The primary endpoint was maximum observed plasma concentration of S-ibuprofen. The registry reports geometric mean summaries and an ANOVA test-to-reference percent ratio of 113.77, with a 90% confidence interval from 98.99 to 130.75. The primary PK population required completion of sampling in both periods and no major protocol deviations considered to affect PK analysis.

The registry lists secondary AUC outcomes and reports no adverse events in its serious or other adverse-event counts for either product. Details on the full analysis model, missing-data handling, multiplicity, and equivalence criteria are not reported in the registry record.