The Single Dose Pharmacokinetics of Two and Proof of Efficacy of One New Etoricoxib Gel Formulation in Participants With Osteoarthritis (MK-0663-168): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Single Dose Pharmacokinetics of Two and Proof of Efficacy of One New Etoricoxib Gel Formulation in Participants With Osteoarthritis (MK-0663-168) (NCT01980940), a randomized phase 1, phase 2 study. The primary outcome is Study Part 1: Maximum Concentration (Cmax) of ETOR After Single Dosing.

2. Clinical Question

3. Trial Design

The registry record describes NCT01980940 as a completed, randomized, double-masked crossover study with Phase 1 and Phase 2 components. It lists enrollment of 70 and identifies osteoarthritis pain as the condition. The study had two distinct parts: a pharmacokinetic assessment after single topical doses, and an efficacy assessment of topical etoricoxib compared with placebo.

In Part 1, participants received etoricoxib 75 mg or 150 mg in 4% DMSO or 4% PG gel. The listed sequences vary the order of these formulations and doses. One sequence includes an etoricoxib 163 mg DMSO application described as an overdose. A separate placebo deviation group comprises participants who received placebo instead of active drug in error and left after the first treatment period; the record says they were included in safety assessments only. These details matter when interpreting the pharmacokinetic population: not every enrolled participant contributed to every active-treatment summary.

Part 2 compared topical etoricoxib 50 mg in 4% DMSO gel, applied twice daily to the affected knee for 2 weeks, with matching placebo. Although the overall study is identified as crossover, the registry record does not report enough information to describe the Part 2 allocation sequence, treatment periods, or any washout arrangements. Those details should not be inferred from the overall design label.

The study began on 2013-12-23, reached primary completion on 2014-11-26, and is listed as completed. Organon and Co is named as sponsor. The posted primary outcome is a pharmacokinetic measure from Part 1. The registry record’s study summary states a separate Part 2 efficacy hypothesis, but posted efficacy estimates and their uncertainty are not reported in the registry record.

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: Participants were screened for inclusion in the study over 4 weeks prior to first treatment. Two additional participants were screened for Study Part 1 but not randomized or treated due to screen failure.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK analysis set defined as all participants treated with etoricoxib with sufficient PK data for reliable estimation of the PK parameter of interest (Cmax) without any protocol violation that interferes with PK data interpretation

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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Study Part 1: Maximum Concentration (Cmax) of ETOR After Single Dosing, measured over Predose and 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 12, 16, 24, 36, 48, and 72 hours post-application.

The primary endpoint is maximum concentration (Cmax) of etoricoxib after a single topical application. It describes the highest measured plasma concentration over the assessment period, which extends through 72 hours after application. Concentration is a pharmacokinetic measure: it characterizes systemic exposure after applying the gel, rather than directly measuring knee pain or function.

The registry record reports Cmax as a geometric least-squares mean, with a 90% confidence interval. Geometric summaries are commonly used for pharmacokinetic quantities because concentrations can be skewed, and multiplicative comparisons can be more natural than differences on the original scale. This is a general statistical explanation, not a claim about an unreported analysis choice beyond the method described in the record. The endpoint description also states that values of 0 were handled by assigning 0.5 times the lower limit of quantification when calculating geometric least-squares means.

Comparing Cmax between formulations can describe how the measured systemic concentration differs by dose and vehicle. It does not by itself establish a clinical effect on pain or function. The study summary separately identifies a Part 2 efficacy question based on time-weighted average change from baseline in the WOMAC VA 3.0 pain subscale over 2 weeks. That is a patient-reported symptom measure and is conceptually distinct from Cmax. Part 2 efficacy results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is summarized using a geometric least-squares mean and a 90% confidence interval. A least-squares mean is a model-based estimate of a group mean, adjusted according to the model’s terms. The registry record identifies ANOVA for the reported treatment-ratio analyses. ANOVA is a general framework for comparing group means while accounting for specified model structure. In a crossover setting, treatment, period, sequence, or participant terms may be relevant, but the registry record does not report the complete model specification. Those terms should not be assumed to have been included.

Geometric summaries are useful for positive measurements that may vary multiplicatively. On the original scale, a few comparatively large concentrations can make an arithmetic mean less representative of the central pattern. A geometric mean is formed on a logarithmic scale and then expressed back on the concentration scale; a geometric least-squares mean similarly reflects a model-based estimate on that scale. This general explanation helps interpret why Cmax results may be presented as geometric estimates. The endpoint description specifically states that values of 0 were handled by substituting 0.5 times the lower limit of quantification for the geometric least-squares mean calculation.

A treatment ratio compares estimates on a multiplicative scale. A ratio is not a difference in concentration units. The registry reports ratios for four formulation and dose comparisons, together with 90% confidence intervals. The posted descriptions do not state the ratio’s numerator and denominator convention, so the ratio should be read in conjunction with the group-level estimates and the stated comparison. The registry reports no p-values for these comparisons. A confidence interval gives a range of values reasonably compatible with the data and model at the stated confidence level; it does not indicate the distribution of individual participants’ concentrations.

The 90% confidence intervals describe uncertainty in the estimated pharmacokinetic quantities. They are narrower or wider in relation to the amount of information and variability in the data, as well as the model. A confidence interval that excludes a particular value can be informative for a contrast when the contrast and its scale are clearly defined. The record does not specify a decision threshold or provide a full inferential plan for the comparisons, so statistical significance should not be inferred from an assumed threshold. Nor should the interval be described as a guarantee that the true value lies within its limits.

The Cmax analysis population is described as participants treated with etoricoxib who had sufficient pharmacokinetic data for reliable estimation and no protocol violation that interfered with interpretation. This is an endpoint-specific analysis population, distinct from total enrollment. The group summaries list 20 participants for ETOR 75 DMSO, 20 for ETOR 75 PG, 20 for ETOR 150 DMSO, and 18 for ETOR 150 PG. The registry record does not explain the difference in group counts or describe the detailed rules for excluding individual observations.

In general, over-dispersion means that observed variability exceeds what a statistical model expects. It can make standard errors too small if not accounted for, leading to intervals that are too narrow and tests that are too optimistic. This is a general concept; the registry record does not identify an over-dispersion assessment or correction for these analyses. Likewise, the record does not report transformations beyond the geometric summary description, model diagnostics, period or carryover assessments, or sensitivity analyses.

Missing-data handling is especially relevant when repeated measurements are taken across a pharmacokinetic profile. Missing concentration observations can affect estimation of Cmax or the shape of the profile. The record gives the assessment time points and the Cmax analysis-population definition, but does not report how missing measurements were handled, how the lower limit of quantification was determined, or whether sensitivity analyses assessed alternative handling choices. These details are not reported in the registry record.

Finally, the registry lists multiple outcomes and analyses, including secondary outcomes for stiffness, physical functioning, patient global assessment, and adverse events. When many outcomes or contrasts are examined, the chance of at least one apparently unusual result can increase unless the analysis plan addresses multiplicity. Whether any adjustment or hierarchical testing strategy was used is not reported in the registry record. The sample-size illustrations associated with the posted results are planning illustrations based on an observed effect under stated assumptions; they are not observed power and are not evidence that the study was designed or justified using those assumptions. The trial’s own sample-size justification is not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s ANOVA treatment-ratio analyses alongside the group Cmax summaries. The four reported ratios are 5.09, 7.30, 0.45, and 0.65, each with a 90% confidence interval. These model-based comparisons are distinct from simply reading the geometric least-squares mean values for each group: the analysis uses a treatment contrast and its model, while the group summaries describe estimated values within treatment groups.

The registry record marks no discrepancy between the sponsor’s results and the associated recalculation. No separate recalculated values are stated in the available record, so there is no additional recalculated estimate to compare with the sponsor’s ratios. The ratio descriptions do not specify which group is the numerator, and that convention should not be guessed. The group summaries can still be read as posted: Cmax estimates are reported for four active formulations, with the DMSO estimates higher than the PG estimates at the corresponding listed doses.

The sponsor’s results take precedence if a discrepancy is identified; no such discrepancy is flagged in this record. This does not resolve other interpretive limits, including the absence of a full model specification and the lack of Part 2 efficacy estimates. The sponsor analysis concerns the posted pharmacokinetic comparisons and should not be treated as a result for the separate pain-efficacy hypothesis.

11. Multiplicity, Missing Data and Analysis Populations

The record lists several outcomes and analyses. In addition to the Part 1 Cmax endpoint, secondary outcomes include changes in WOMAC stiffness and physical functioning, categories of patient global assessment, and adverse-event measures. The registry reports 9 outcome measures and 29 analyses. With multiple outcomes or treatment contrasts, the overall chance of obtaining at least one apparently noteworthy result may be higher than for a single prespecified comparison. Statistical procedures can address this concern, but the approach used for this study is not reported in the registry record.

The listed primary endpoint is a pharmacokinetic outcome, while the study summary describes an efficacy hypothesis for Part 2 using time-weighted average change from baseline on the WOMAC VA 3.0 pain subscale over 2 weeks. Results for that efficacy question are not reported in the registry record. It is therefore not possible to assess its estimated treatment effect, uncertainty, or relationship to the secondary efficacy outcomes from the posted results.

The registry record defines a pharmacokinetic analysis population based on treatment, sufficient data for reliable Cmax estimation, and the absence of a protocol violation that interferes with interpretation. It does not report the full analysis populations for efficacy outcomes or the detailed handling of missing data. The Part 1 placebo deviation group is described as safety-only, and the overdose group has no estimable Cmax summary. The record does not report whether missing concentration values were imputed, excluded, or handled by another method, nor does it describe sensitivity analyses.

Interim analyses, stopping rules, and the statistical plan for multiplicity are not reported in the registry record. The trial’s own sample-size justification is also not reported in the registry record. Any sample-size figures used for planning illustrations are not observed power and should not be interpreted as proof that the study had a particular probability of detecting an effect. Without the full prespecified analysis plan, the posted estimates can be described, but the degree to which they reflect a complete confirmatory testing strategy cannot be determined.

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.

Most frequent non-serious adverse event terms

The safety listings report no serious adverse events for any listed group: the serious-event count is 0 in each group. The corresponding numbers at risk are 20 for each of the four main Part 1 active formulation groups, 2 for the Part 1 overdose group, 2 for the Part 1 placebo deviation group, and 24 for each Part 2 group. These counts describe what was recorded in the safety summaries; they do not establish that serious events could not occur or that the groups had equivalent safety.

For other adverse events, the listing reports 0 for ETOR 75 DMSO, ETOR 75 PG, and ETOR 150 DMSO; 1 for ETOR 150 PG; 2 for ETOR OD; 0 for the Part 1 placebo deviation group; and 2 each for ETOR 50 DMSO and placebo in Part 2. The record presents these as participant counts, not as estimates adjusted for exposure time or treatment order. The Part 1 treatment sequences and Part 2 treatment duration differ, so the raw counts should not be interpreted as directly comparable rates.

Death values are not reported in the registry record. The safety data are descriptive and include small group counts. They do not establish causal attribution for individual events, and the listed counts alone do not support a conclusion that one treatment is safer than another.

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

The posted results establish that the registry reports measurable plasma Cmax summaries for four etoricoxib gel conditions: 75 mg and 150 mg in DMSO or PG formulations. They also provide model-based treatment ratios and 90% confidence intervals for comparisons among those conditions. The summaries indicate differences in measured systemic exposure across the listed formulations and doses. They do not directly measure pain relief, physical function, or treatment response.

The study’s summary describes a Part 2 question about topical etoricoxib compared with placebo for osteoarthritis of the knee, using time-weighted average change from baseline in the WOMAC pain subscale over 2 weeks. However, results for that efficacy question are not reported in the registry record. The primary result currently available is the Part 1 pharmacokinetic endpoint. A pharmacokinetic estimate cannot substitute for an efficacy estimate, and the posted Cmax results do not establish whether symptoms changed in either Part 2 group.

The reported confidence intervals show uncertainty around the estimated Cmax values and treatment ratios. They do not describe the range of individual responses, and they do not account for uncertainties that may arise from unreported model details, missing-data handling, or multiplicity procedures. The analysis population is limited to participants meeting the stated pharmacokinetic-data criteria, so the group counts should not be confused with total enrollment.

The safety listing records no serious adverse events in the listed groups and reports some other adverse events. These are descriptive counts from the registry record, not a definitive comparison of safety. Small group counts and differences in treatment duration and sequence limit what can be inferred from raw event counts. Taken together, the posted results are informative about the measured pharmacokinetic profiles and the reported event counts, but they do not answer the Part 2 symptom-efficacy question or support a broad conclusion about clinical benefit or risk.

14. Why This Trial Matters Statistically

This study illustrates why clinical trial endpoints need to be read in the context of the question they measure. Cmax describes systemic exposure after topical application. It can help characterize absorption and compare formulations, but it is not a patient-centered symptom outcome. The trial summary also describes a pain-efficacy question, yet the posted primary results concern pharmacokinetics. Keeping those questions separate prevents a concentration difference from being mistaken for an improvement in pain or function.

The study also illustrates how a crossover design can make treatment comparisons within a study, while requiring careful attention to treatment sequence, periods, and participant-level analysis. The record lists sequences and labels the overall design as crossover, but does not report the complete statistical model or operational details needed to evaluate possible period or carryover effects. A design label alone is not a substitute for those details.

Geometric least-squares means and treatment ratios are natural ways to report concentration outcomes that are analyzed on a multiplicative scale. Their interpretation depends on the specified contrast and ratio convention. Reporting confidence intervals alongside point estimates helps convey uncertainty, but the intervals cannot fill gaps in the analysis description or replace results for an unreported endpoint.

Finally, the record shows why registry completeness matters. It lists multiple outcomes and analyses, while multiplicity procedures, missing-data handling, interim analyses, and the study’s own sample-size justification are not reported in the registry record. Such information is important for judging how planned comparisons relate to posted results. The pharmacokinetic estimates remain interpretable as reported, but their scope should stay tied to the endpoint and population actually analyzed.

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 features of this particular record constrain interpretation. The primary posted outcome is Part 1 Cmax, even though the study summary also states a Part 2 efficacy hypothesis. Efficacy estimates for the WOMAC pain question are not reported in the registry record, so the study’s symptom-treatment comparison cannot be assessed from these results.

The crossover sequences are described, but the registry record does not report the full sequence allocation details, period structure, washout arrangements, or the complete ANOVA model. This makes it difficult to assess how the analysis accounted for repeated treatment periods or whether period and carryover considerations were evaluated. The treatment-ratio descriptions also do not specify numerator and denominator conventions.

Some Part 1 groups have no Cmax estimate: the overdose and placebo deviation groups. The placebo deviation participants are described as safety-only, while the overdose group includes a small number of participants in the safety listing. The posted summaries therefore do not provide a complete pharmacokinetic estimate for every sequence or exposure described in the record. The group counts for estimable Cmax values are smaller than the total enrollment, and the reasons for all group-count differences are not reported in the registry record.

The record does not report detailed missing-data procedures, model diagnostics, sensitivity analyses, multiplicity handling, interim analyses, or the study’s own sample-size justification. It also does not report death counts. Safety findings are presented as counts across groups with different treatment contexts and durations, so they should not be treated as adjusted comparative rates. These limitations do not erase the posted estimates, but they restrict conclusions to the specific summaries and groups reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Single Dose Pharmacokinetics of Two and Proof of Efficacy of One New Etoricoxib Gel Formulation in Participants With Osteoarthritis (MK-0663-168) — NCT01980940.
• Registry record last updated 2024-06-27; status last verified 2022-02.
• Results first posted 2015-12-11.
• 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

NCT01980940 is a completed randomized, double-masked crossover study with Phase 1 and Phase 2 components and enrollment of 70. Part 1 assessed plasma pharmacokinetics after single topical applications of etoricoxib 75 mg or 150 mg in DMSO or PG gel. Part 2 compared etoricoxib 50 mg in DMSO gel, applied twice daily for 2 weeks, with matching placebo.

The posted primary endpoint is Cmax through 72 hours after application, summarized as geometric least-squares means with 90% confidence intervals. The registry reports four ANOVA treatment ratios for formulation and dose comparisons. Part 2 efficacy results are not reported in the registry record. The safety listing reports no serious adverse events in the listed groups and reports other adverse-event counts across the Part 1 and Part 2 groups.