A Comparative Study Between PF-06410293 and Humira® in Combination With Methotrexate in Participants With Active Rheumatoid Arthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Comparative Study Between PF-06410293 and Humira® in Combination With Methotrexate in Participants With Active Rheumatoid Arthritis (NCT04230213), a randomized phase 3 study. The primary outcome is Maximum Observed Serum Concentration (Cmax) of Adalimumab.

2. Clinical Question

The study is framed around pharmacokinetics, safety, and immunogenicity after switching between PF-06410293 and adalimumab, compared with continuous adalimumab, in combination with methotrexate. The primary endpoint focuses specifically on the maximum observed serum concentration of adalimumab, rather than a clinical disease-activity measure. It therefore addresses whether the arms had similar observed drug-concentration profiles at the stated assessment, not whether participants experienced the same clinical course.

The registry record describes a randomized study with parallel groups and no masking. It does not report the detailed switching sequence or the schedule of each drug across the full study. Those details should not be inferred from the arm labels or from the every-other-week dosing descriptions.

3. Trial Design

This was a phase 3, randomized, parallel-group study of PF-06410293 and adalimumab in participants with rheumatoid arthritis. The registry record lists an enrollment of 455 and a completed study. The recorded start was 2020-01-13, and primary completion was 2021-06-22. These dates describe the trial record and do not by themselves explain how long any individual participant was followed.

One arm is labeled the Switching Arm and involved Humira and PF-06410293; the other is labeled the Non-switching Arm and involved Humira. Both arm descriptions specify subcutaneous injection every other week. Methotrexate is part of the study’s stated treatment context and is also required for inclusion in the primary pharmacokinetic population described in the endpoint record. The specific switching sequence and timing are not reported in the registry record.

The primary pharmacokinetic analysis included 194 participants in the switching arm and 186 in the non-switching arm. These analysis counts are distinct from the overall enrollment and should not be treated as a complete account of every analysis population. For the reported safety outcomes, the registry lists 213 participants in the switching arm and 214 in the non-switching arm. The record also gives a separate 445-participant Humira safety grouping. The relationship between that grouping and the treatment-period safety groups is not explained in the registry record.

Randomization can help create comparable groups, while a parallel design follows separate groups rather than having each participant receive both assigned strategies in sequence. No masking was used. The method of randomization, allocation concealment, stratification factors, and detailed follow-up schedule 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: A total of 455 participants were enrolled in the study of which 10 participants were excluded from all the data analyses due to violation of Good Clinical Practice (GCP) principles. These 10 participants were not included in any section of results.

TP1: Week 0 (Day 1) to Week 10

Reasons for not completing this period:

TP2: Week 10 to Week 16

Reasons for not completing this period:

TP3: Week 16 to Week 22

Reasons for not completing this period:

TP4: Week 22 to Week 32

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population included all randomized participants who were dosed to initiate the week 30 steady-state PK profile and remained on background methotrexate with no major protocol deviations influencing the PK assessment. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure. Since time points for analysis for this outcome measure were falling in TP4, hence only switching and non-switching arms data were reported.

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 analysis population included all the participants who were enrolled in TP1.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Serum Concentration (Cmax) of Adalimumab, measured over Pre-dose, 48, 72, 96, 144, 240 and 336 hours post dose on Day 211 (Week 30).

The primary endpoint is the maximum observed serum concentration, or Cmax, of adalimumab. It is measured in micrograms per milliliter. The Week 30 profile included measurements before dosing and at 48, 72, 96, 144, 240, and 336 hours after the dose on Day 211. Cmax is the highest observed concentration among the scheduled measurements in that profile. It is a pharmacokinetic measure: it describes drug concentration in serum, not symptom improvement or another direct clinical outcome.

The registry reports geometric means and geometric coefficients of variation for the arms. A geometric mean is commonly used for positive concentration measurements that may be distributed asymmetrically. The geometric coefficient of variation describes relative variability on a percentage scale; the reported value for each arm is 97. The registry’s population definition narrows the analysis to randomized participants who were dosed to initiate the Week 30 steady-state profile, remained on background methotrexate, and had no major protocol deviations influencing the pharmacokinetic assessment.

Comparing Cmax can help characterize whether two treatment strategies produce similar observed serum exposure at the selected assessment. It does not by itself establish similarity for every pharmacokinetic feature, such as the timing of peak concentration or average concentration, and it does not establish the same safety or clinical outcomes. Those questions require their own outcome definitions and analyses.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For the primary endpoint, the registry presents a geometric mean for each arm and a geometric mean ratio with a 90% confidence interval. The reported geometric means are 9.156 for the switching arm and 8.974 for the non-switching arm, in micrograms per milliliter. The ratio estimate is 102.56%, and its interval is 89.78% to 117.17%. These values describe a comparison of concentrations on a multiplicative scale, a common approach for positive pharmacokinetic measurements.

Why use a geometric mean?

In general, concentration measurements are positive and can have a right-skewed distribution: a smaller number of high values may stretch the upper end of the distribution. A geometric mean is based on logarithmic values and can be appropriate for that pattern. A ratio of geometric means then expresses the relative concentration between arms. This is different from a difference between ordinary arithmetic averages, so the ratio should be interpreted on its own scale.

The geometric coefficient of variation is a measure of relative spread for the concentration data. Both arms have a reported geometric coefficient of variation of 97%. It is not a confidence interval for the arm mean and does not describe the range containing most individual participants. The registry does not report additional distribution summaries for this endpoint.

What does the confidence interval convey?

In general, a confidence interval reflects sampling uncertainty under a specified statistical procedure and its assumptions. A narrower interval indicates greater precision than a wider interval on the same scale. The 90% interval for the ratio spans 89.78% to 117.17%. Its interpretation depends on the method used to calculate it; the detailed calculation method is not reported in the registry record. The interval provides more information about precision than the point estimate alone, but it cannot establish equivalence without the prespecified margins.

Equivalence testing asks whether the data are sufficiently precise to exclude differences outside a prespecified acceptable range. The acceptable range is defined by equivalence margins. The registry labels the reported analysis as equivalence but does not state those margins, so the formal decision rule cannot be reconstructed from the record. A ratio near 100% is not, on its own, proof of equivalence.

How should the other comparisons be read?

The registry also posts participant counts for two secondary outcomes after the later treatment period: Grade 3 or higher treatment-emergent adverse events and adverse events of special interest. The posted recalculations express arm comparisons as risk differences and provide confidence intervals and unadjusted p-values. A risk difference is the difference between the observed proportions in the two groups, expressed on an absolute scale. In general, its confidence interval indicates the range of differences compatible with the data under the interval method; an interval spanning zero does not rule out either direction of difference.

These secondary comparisons are unadjusted. In general, when many outcomes are tested, the chance of at least one apparently notable result can increase if no allowance is made for multiple testing. An unadjusted p-value addresses an individual comparison under its own assumptions; it does not account for the full set of outcomes. The registry record does not report a multiplicity adjustment or a prespecified hierarchy for these posted results.

The sample-size illustrations attached to the secondary comparisons are planning calculations based on observed effects, not observed power and not the trial’s original design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The illustrations use specified fractions of the observed effect. In general, these calculations show how required enrollment can change under assumed effects and design conditions; they do not establish that the trial was adequately or inadequately powered for its original objectives. The trial’s own sample-size justification is not reported in the registry record.

What methods are not specified?

The registry record does not report the statistical methods used for the sponsor’s primary analysis, the equivalence margins, how missing observations were handled, or whether interim analyses were conducted. It also does not report a formal statistical analysis plan for the posted secondary comparisons. These omissions limit independent reconstruction of the analyses and make it important to distinguish the reported estimates from assumptions that cannot be verified from this record.

10. Analyses Reported by the Sponsor

The sponsor-reported primary comparison is a geometric mean ratio of 102.56%, with a 90% confidence interval from 89.78% to 117.17%. This is the analysis identified in the registry as an equivalence analysis. The record gives no p-value and does not state the equivalence margins, so the formal equivalence decision rule cannot be assessed from the registry record alone.

The arm-level geometric means are 9.156 and 8.974 micrograms per milliliter, with a geometric coefficient of variation of 97% in each arm. These summaries are consistent in direction with a ratio estimate near 100%, but the interval is necessary to understand the uncertainty around that estimate. Similar point estimates do not, by themselves, demonstrate that a prespecified equivalence criterion was met.

The posted recalculations are unadjusted calculations from summary statistics and are not substitutes for the sponsor’s analysis. No discrepancy is flagged for the primary result. The sponsor’s own analysis is the relevant reported analysis for the endpoint, while the available record still lacks details needed to independently reproduce its method or evaluate the equivalence margins.

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report whether the primary endpoint was part of a prespecified testing hierarchy, how the secondary outcomes were prioritized, or whether any adjustment for multiple comparisons was planned or applied. It lists 31 outcome measures and 29 posted secondary outcomes, but the number of posted outcomes alone does not establish which were confirmatory or how they were to be interpreted. The record also does not report interim analyses or stopping rules.

This matters because statistical evidence from many separate comparisons is not equivalent to evidence from a single prespecified comparison. In general, if repeated tests are considered without adjustment, the chance of at least one apparently unusual result can rise. An unadjusted p-value describes evidence for its particular comparison, not the probability that a result across the entire collection of outcomes is a false positive. The secondary comparisons should therefore be interpreted cautiously, especially in the absence of a reported analysis hierarchy.

Missing-data handling is not reported in the registry record. The record gives endpoint-specific analysis counts and defines the primary pharmacokinetic population, but it does not explain how participants without an evaluable profile were handled, whether any data were imputed, or how missing secondary outcome information was treated. Those details can affect both the population represented by an estimate and its uncertainty.

The primary population is not simply described as everyone randomized. It comprises randomized participants who were dosed to initiate the Week 30 steady-state profile, remained on background methotrexate, and had no major protocol deviations influencing the pharmacokinetic assessment. This definition is relevant when applying the result: it is an analysis of participants meeting those criteria, rather than necessarily a full intention-to-treat comparison. The registry record does not provide a separate intention-to-treat result for the primary endpoint.

The sample-size justification, detailed statistical analysis plan, equivalence margins, and sponsor-analysis methods are also not reported in the registry record. As a result, the record does not permit full assessment of prespecification, missing-data sensitivity, multiplicity control, or whether all planned analyses are represented in the posted results.

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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: covid-19 (1.1%), covid-19 pneumonia (0.9%), keratitis (0.5%), abscess limb (0.5%), pneumonia (0.5%).

The registry reports serious adverse events for a Humira grouping with 445 participants at risk, in which 13 participants were affected. In the later treatment-period arm groups, 3 of 213 participants in the switching arm and 8 of 214 in the non-switching arm were reported with serious adverse events. The record also lists other adverse events separately: 28 of 445 in the Humira grouping, 46 of 213 in the switching arm, and 38 of 214 in the non-switching arm. No deaths are listed in any of these groups.

These are counts of participants, not counts of all event episodes. The registry does not explain the relationship between the 445-participant Humira grouping and the two later-period treatment groups, so they should not be combined or treated as interchangeable denominators. Serious adverse events and other adverse events are also distinct categories and should not be conflated.

The listed serious-event terms include COVID-19 at 1.1%, COVID-19 pneumonia at 0.9%, keratitis at 0.5%, abscess limb at 0.5%, pneumonia at 0.5%, and blood loss anaemia at 0.5%. These percentages are reported terms in the record; the detailed event-level context is not reported. Safety counts describe what was recorded in these groups and do not, by themselves, establish a causal relationship or a comparative safety conclusion.

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

The primary finding is an estimated comparison of adalimumab maximum serum concentration at the Week 30 steady-state profile. The reported geometric mean ratio is 102.56%, with a 90% confidence interval of 89.78% to 117.17%. This describes the relative Cmax estimates for the defined pharmacokinetic population. It is not a measure of disease activity, symptom change, or a participant’s overall response.

The registry labels the analysis as equivalence, but the equivalence margins are not reported. Consequently, the posted ratio and interval do not allow a reader to verify whether a prespecified equivalence threshold was met. The interval shows uncertainty around the ratio under the sponsor’s reported analysis; it does not answer every question about exposure, and it does not establish clinical equivalence between treatment strategies.

The findings also do not show that every participant had similar concentrations. The geometric coefficients of variation are 97% in both arms, indicating substantial relative variability in the concentration measurements. Group summaries do not describe the complete distribution of individual values. Nor does a similar Cmax estimate demonstrate similar results for other pharmacokinetic measures, safety outcomes, immunogenicity, or clinical outcomes.

Safety counts and secondary comparisons provide information on separate outcomes, with their own denominators, timeframes, and limitations. They should not be interpreted as if they were components of the primary Cmax comparison. The secondary comparisons are unadjusted, and the registry does not report how multiplicity was handled. The safety figures likewise do not establish that any event was caused by a treatment.

In general, a randomized comparison supports interpretation of group differences within the trial’s design and analyzed population. The record’s available results do not supply the equivalence margins, complete analysis plan, missing-data methods, or detailed switching schedule. Those limits constrain how broadly the findings can be interpreted and prevent a full independent reconstruction of the sponsor’s analysis.

14. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is framed around equivalence in a pharmacokinetic measure, rather than superiority on a clinical outcome. Equivalence requires a defined acceptable range and enough precision to rule out differences beyond that range. The reported ratio and confidence interval are central to that reasoning, but the registry record does not give the margins needed to evaluate the formal criterion.

The result also shows why a point estimate alone is insufficient. A ratio estimate near 100% can look similar at a glance, while the confidence interval communicates the range of estimates compatible with the data under the reported procedure. The arm-specific geometric coefficients of variation further indicate that individual concentration measurements vary substantially relative to their geometric means. In general, variability and precision are related but not identical: the interval for the group comparison is needed to assess the latter.

The analysis population is another important statistical feature. The primary result applies to randomized participants who initiated the Week 30 profile, remained on background methotrexate, and had no major protocol deviations affecting the assessment. That carefully defined population is not necessarily equivalent to all randomized participants. Readers need the population definition to understand the scope of the estimate.

Finally, the record includes numerous outcomes and secondary comparisons, but does not report a multiplicity strategy or a detailed analysis plan. This underscores the need to distinguish a primary pharmacokinetic estimate from unadjusted secondary findings and descriptive safety counts. Statistical interpretation depends not only on numerical estimates, but also on the estimand, analysis population, uncertainty, and prespecified decision rules.

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 record leaves several trial-specific details unresolved. It does not report the equivalence margins for the primary analysis, so the formal equivalence criterion cannot be checked against the confidence interval. It also does not report the sponsor’s detailed statistical method, the trial’s sample-size justification, or whether interim analyses occurred. These gaps limit assessment of the design rationale and independent reproducibility.

The primary analysis population is restricted to participants who were dosed to initiate the Week 30 steady-state profile, remained on background methotrexate, and had no major protocol deviations influencing the pharmacokinetic assessment. The record does not report a separate all-randomized analysis for this endpoint or describe the effect of excluding participants who did not meet these criteria. Missing-data methods are not reported, so the impact of unavailable or unevaluable measurements cannot be assessed from the registry record.

The registry describes the arms as switching and non-switching but does not provide the detailed switching sequence or timing. Although both arm descriptions specify subcutaneous injections every other week, that alone is not a complete description of the treatment schedule. Masking was not used, and the record does not report allocation concealment or other randomization details.

The secondary comparisons are unadjusted, and no multiplicity approach or confirmatory hierarchy is reported. Safety populations also include a 445-participant Humira grouping alongside separate later-period treatment groups; their relationship is not explained. Finally, the primary endpoint is a pharmacokinetic measure, and the registry information does not establish that its result predicts clinical outcomes or captures all relevant safety and immunogenicity questions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Comparative Study Between PF-06410293 and Humira® in Combination With Methotrexate in Participants With Active Rheumatoid Arthritis — NCT04230213.
• Registry record last updated 2024-02-22; status last verified 2024-01.
• Results first posted 2022-08-22.
• 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, parallel-group phase 3 study in participants with moderately to severely active rheumatoid arthritis. The study compared a switching arm involving PF-06410293 and Humira with a non-switching Humira arm, in the context of methotrexate treatment. The registry lists enrollment of 455 and no masking.

The primary endpoint was adalimumab Cmax at the Week 30 steady-state profile. The sponsor-reported geometric mean ratio was 102.56%, with a 90% confidence interval of 89.78% to 117.17%. The registry labels the analysis as equivalence, but does not report the equivalence margins. Safety and other secondary outcomes are also posted; the secondary comparisons are unadjusted, and the record does not report a multiplicity strategy or missing-data methods.