Study in Subjects With Rheumatoid Arthritis to Evaluate the Effect of a Single Dose of Olokizumab on the Pharmacokinetics of Substrates for CYP1A2, CYP2C9, CYP2C19 and CYP3A4: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study in Subjects With Rheumatoid Arthritis to Evaluate the Effect of a Single Dose of Olokizumab on the Pharmacokinetics of Substrates for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 (NCT04246762), a na phase 1 study. The primary outcome is Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC(0-inf)) for Caffeine, Omeprazole and Midazolam.

2. Clinical Question

The underlying rationale described in the registry record is that olokizumab had reversed an inhibitory effect of IL-6 on several CYP450 isozyme activities in vitro. The clinical question was whether the pharmacokinetics of selected probe substrates differed in subjects with rheumatoid arthritis in the context of olokizumab dosing. The record does not report a randomized control group, so the study is not designed as a like-for-like comparison of olokizumab with placebo or another treatment.

3. Trial Design

The registry record identifies this as a Phase 1, open-label, single-group study in subjects with rheumatoid arthritis. It reports enrollment of 17 and a completed status. The recorded study start was 2021-11-16, and primary completion was 2022-06-08. Allocation is listed as not applicable, consistent with the absence of a randomized comparison; masking is listed as none.

The listed regimen includes a cocktail of omeprazole, caffeine, warfarin with vitamin K solution, and midazolam, administered orally with 240 mL of water on Day 1. A single subcutaneous injection of olokizumab 128 mg was administered on Day 8. The primary outcome schedule identifies pharmacokinetic sampling on Day 1 and Day 22, with samples before dosing and at multiple post-dose times. The registry record does not fully describe the later cocktail administration in the available arm description, so its complete schedule is not reported in the registry record.

The probe-drug approach allows investigators to assess pharmacokinetic measures associated with several CYP450 pathways in one study. The primary outcome concerns AUC for caffeine, omeprazole, and midazolam; secondary outcomes include additional pharmacokinetic measures and S-warfarin AUC. This is a descriptive design focused on pharmacokinetic measurements rather than a randomized treatment-efficacy comparison.

The registry record does not report the sample-size justification, detailed eligibility criteria, or a full statistical analysis plan. It also does not report whether any interim analyses were planned or conducted. The planning illustrations associated with the analysis use assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those are hypothetical planning assumptions and do not describe the actual single-group design or establish observed power.

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.

Period 1: Cocktail Alone

Reasons for not completing this period:

Period 2: Olokizumab Administration

Period 3: Olokizumab + Cocktail

Safety Follow-up

Analysis population for the primary outcome, as defined in the registry: These subjects were excluded: For 1 subject the Percentage of AUC(0-inf) obtained by extrapolation (%AUCex) was \> 20.0 % for midazolam on Day 1. 1 subject had a quantifiable predose concentration of Omeprazole on Day 1 that exceeded 5% of Cmax. For 3 subjects the %AUCex exceeded 20.0 % for baseline-adjusted caffeine on Day 22 and for 1 subject - on Day 1 also. For 1 subject λz calculated from the observed caffeine concentration data on Day 1 was not adequate for baseline adjustment purposes.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC(0-inf)) for Caffeine, Omeprazole and Midazolam, measured over Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24 (Day 2), 30 (Day 2, only caffeine) hours post-dose; Day 22: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24 (Day 23), 30 (Day 23, only caffeine) hours post-dose.

The primary endpoint is the area under the plasma concentration-time curve from time zero extrapolated to infinity, or AUC(0-inf), for caffeine, omeprazole, and midazolam. AUC represents overall drug exposure across the measured concentration-time profile. Extending the area to infinity accounts for the estimated portion of exposure after the final measured concentration, so the value depends both on observed concentrations and on the extrapolation procedure.

The registry record specifies calculation by linear up/log down trapezoidal summation. It reports geometric least-squares means and 95% confidence intervals as the endpoint summary. A geometric mean is suitable for positive pharmacokinetic measures that may be asymmetric on their original scale; it summarizes values on a multiplicative scale. A confidence interval conveys uncertainty around an estimated quantity, rather than the range of individual participants' values. Without the numerical estimates and intervals, the magnitude and precision of the primary outcome cannot be evaluated from the registry record.

The probe drugs connect the outcome to particular metabolic pathways: caffeine is the CYP1A2 probe, omeprazole the CYP2C19 probe, and midazolam the CYP3A4 probe. S-warfarin, associated with CYP2C9, is listed among secondary outcomes rather than the primary endpoint. The endpoint is therefore a pharmacokinetic measure, not a direct measure of symptoms, disease activity, or clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record characterizes the primary endpoint as a geometric least-squares mean with a 95% confidence interval. These are statistical summaries of pharmacokinetic measurements. A geometric mean summarizes positive values after taking logarithms, then expresses the resulting average on the original scale. This is useful in general when values are right-skewed or when proportional changes are more natural to interpret than additive changes. A least-squares mean is an estimate produced by a statistical model, potentially adjusted for terms in that model. The model details and the exact contrast represented by the reported primary summaries are not reported in the registry record.

A 95% confidence interval describes uncertainty in an estimated quantity under the analysis assumptions. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. It is not a range containing 95% of individual participant values. Because the actual estimates and intervals are not reported in the registry record, their widths and the precision of the study estimates cannot be assessed.

How is AUC calculated?

AUC is the area under a concentration-time curve and summarizes exposure over time. The record specifies linear up/log down trapezoidal summation: in general, this uses linear interpolation for rising concentrations and logarithmic interpolation for falling concentrations between measured points. AUC(0-inf) combines the area over the observed sampling period with an extrapolated tail after the last measured concentration. That tail is estimated from the terminal decline in concentration, so reliability can depend on the available measurements and the estimated terminal elimination rate.

The registry defines an exclusion criterion for an extrapolated share of AUC above 20.0%. It reports that 1 subject exceeded this threshold for midazolam on Day 1. The population description also begins to report exclusions for 3 subjects based on %AUCex, but the affected analyte and occasion are not reported in the registry record. A large extrapolated share can make the total AUC more dependent on modeling beyond observed data; this is a general reason to treat such estimates cautiously.

Why adjust caffeine concentrations?

Caffeine is common in foods and beverages, and the registry says most subjects had predose caffeine concentrations on Day 1 and Day 22 exceeding 5% of Cmax. The described calculation subtracts an estimated residual predose contribution at each post-dose timepoint. The estimate uses the predose concentration, a participant-specific elimination rate constant, and elapsed time after dosing. In general, this adjustment aims to distinguish exposure from the study dose from caffeine already present before dosing. It relies on the accuracy of the estimated elimination rate and on the stated model for the decline of predose caffeine.

The record also says that a subject's pharmacokinetic parameters for an affected analyte were excluded when an anomalous predose concentration exceeded 5% of Cmax. It separately identifies 1 subject with a quantifiable predose omeprazole concentration on Day 1 above this threshold. These rules address potential contamination of post-dose measurements by drug already present before the planned dose. The record does not report all final analysis populations or the resulting counts by analyte and timepoint.

What do probe substrates contribute?

The cocktail contains drugs used as probes for different CYP450 enzymes: caffeine for CYP1A2, S-warfarin for CYP2C9, omeprazole for CYP2C19, and midazolam for CYP3A4. In general, pharmacokinetic changes in a probe substrate can help characterize enzyme-related drug handling. They do not by themselves establish clinical consequences for every other medicine metabolized through the same pathway. The registry lists AUC(0-inf) for caffeine, omeprazole, and midazolam as primary, while S-warfarin AUC(0-inf) and other pharmacokinetic measures are secondary.

The record names eight analyses and 13 outcome measures, but a complete statistical analysis plan is not reported in the registry record. The exact model specification, handling of repeated measurements, and method for constructing the least-squares means are not reported. The sample-size planning assumptions describe a two-arm normal-approximation illustration with equal allocation and a two-sided significance level of 0.05. Since the actual study is single-group, such an illustration is not a description of its allocation and is not observed power.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 13 outcome measures and eight analyses, including several pharmacokinetic endpoints and multiple probe drugs. Testing or estimating multiple outcomes raises a multiplicity question: in general, the chance of at least one apparently notable result can increase when many hypotheses are considered. The registry record does not report whether a multiplicity adjustment, hierarchy of endpoints, or other prespecified strategy was used. It also does not report the complete statistical analysis plan, so the intended interpretation across the several analyses cannot be reconstructed.

Missingness and exclusions are especially relevant to pharmacokinetic measurements because AUC depends on a sequence of concentration samples. The record specifies that anomalous predose concentrations above 5% of Cmax could lead to exclusion of affected analyte parameters. It also identifies one midazolam Day 1 case with %AUCex above 20.0%, one Day 1 omeprazole predose case above the stated threshold, and begins to describe %AUCex exclusions for 3 subjects. The analyte and occasion for that latter group are not reported in the registry record. Final analyzed counts by outcome are not reported in the registry record.

The record does not describe how missing individual concentration samples were handled, whether any values were imputed, or whether sensitivity analyses assessed the effect of exclusions. Those details are not reported in the registry record. In general, excluding a participant or an analyte-specific profile can change the set of observations contributing to an estimate, and the implications depend on why measurements are unavailable or excluded.

The record's safety figures list 17 participants at risk for both serious and other adverse events. It does not give additional detail on missing safety observations or event-specific analysis methods. No interim-analysis plan is reported in the registry record. These omissions limit assessment of how comprehensively the statistical decisions were prespecified and how the reported analysis populations relate to enrollment.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry record lists 17 participants at risk for serious adverse events and 0 affected. It lists the same 17 at risk for other adverse events and 6 affected. Deaths are listed as 0. No serious adverse-event terms are listed in the record. These are counts for the study group, not a comparison between olokizumab and a control group.

In general, an adverse-event count describes what was recorded during the study and does not establish that an event was caused by a study drug. The registry figures do not provide event descriptions, severity details for the other adverse events, timing, or participant-level overlap among events. They also do not supply a comparator rate. As a result, the counts should be read as descriptive safety information from a small single-group study, not as a comparative estimate of risk.

The absence of listed serious adverse events or deaths in this record is not proof that such events cannot occur, nor does it establish overall safety. The registry record does not report enough detail to assess event patterns or relate events to the timing of olokizumab and the probe-drug cocktail.

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

This study addresses a pharmacokinetic question: whether exposure to selected CYP450 probe drugs differed in the study schedule around a single dose of olokizumab. Its primary outcome is AUC(0-inf) for caffeine, omeprazole, and midazolam, with other pharmacokinetic measures and S-warfarin listed as secondary outcomes. The use of probe substrates gives the study a focused laboratory and pharmacokinetic purpose.

The registry record does not report numerical primary outcome estimates or their confidence intervals. Therefore, it does not support a statement about the direction, magnitude, or precision of the observed pharmacokinetic findings. Completion status and a stated study objective are not substitutes for outcome results.

Even if numerical pharmacokinetic results were available, their scope would remain specific to the studied subjects, dosing schedule, probe drugs, and measures. In general, a change in exposure to a probe substrate does not automatically predict the effect on every other medication processed by the same enzyme. Nor is a pharmacokinetic endpoint itself evidence about symptom improvement, rheumatoid arthritis disease control, or other clinical outcomes.

The single-group, open-label design also limits causal interpretation. Measurements on different study days can describe within-study patterns, but without a concurrent randomized control group they cannot separate the effect associated with olokizumab from other time-related influences. The registry record does not report a protocol-level justification for sample size or a full statistical analysis plan. The safety counts are descriptive and likewise do not provide a controlled estimate of comparative risk.

The appropriate reading is therefore narrow: the registry records a completed Phase 1 investigation of olokizumab and probe-drug pharmacokinetics in subjects with rheumatoid arthritis, with specified AUC methods and data-handling rules. The numerical pharmacokinetic conclusions are not reported in the registry record, so claims about what the study found on its primary question are not supported by the posted information.

13. Why This Trial Matters Statistically

This study is statistically interesting because it uses a probe-drug cocktail to examine several enzyme pathways within a focused pharmacokinetic investigation. The primary endpoints target CYP1A2, CYP2C19, and CYP3A4 through caffeine, omeprazole, and midazolam. Secondary outcomes include S-warfarin for CYP2C9, along with additional measures such as time to maximum concentration, terminal half-life, elimination rate constant, apparent clearance, and apparent volume of distribution.

The design also illustrates why pharmacokinetic analysis depends on more than the final summary measure. AUC(0-inf) combines observed concentration data with an extrapolated component. The registry's threshold for %AUCex and its handling of predose concentrations show how data quality and modeling decisions can determine which profiles are considered interpretable. Caffeine presents a particular measurement issue because predose levels were common, leading to the described adjustment for residual caffeine.

The record is also a useful example of the boundary between a biological rationale and a clinical result. The stated rationale refers to in vitro reversal of IL-6 inhibition of CYP activity, while the study objective concerns pharmacokinetic measurements in subjects. These are distinct kinds of evidence. The registry record's numerical outcome results are not reported, so the statistical question cannot be resolved from the recorded information alone.

Finally, the single-group, open-label structure is important when interpreting any within-study measurements. Such a design can characterize pharmacokinetic observations under the study schedule, but it does not offer the same protection against alternative explanations as a randomized controlled comparison. The study therefore highlights the value of clearly reported estimates, uncertainty intervals, analysis populations, and prespecified methods for interpreting pharmacokinetic evidence.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most consequential limitation of the registry information is that numerical primary outcome results are not reported in the registry record. Without the geometric least-squares means, confidence intervals, or analyzed sample counts, the estimated effect and its precision cannot be assessed. The record identifies the endpoint and methods but does not supply the results needed to answer the study's central pharmacokinetic question.

The study is listed as open-label and single-group, with no randomized allocation. Day 1 and Day 22 sampling around the Day 8 olokizumab dose can provide timed measurements, but there is no concurrent control group in the design description. This limits separation of any changes associated with olokizumab from other influences over time. The record does not report blinding or a randomized comparator.

Pharmacokinetic estimates may be sensitive to exclusions and extrapolation. The registry describes predose concentration thresholds and an %AUCex threshold, and identifies some affected profiles. However, final analyzable counts by drug and timepoint, the complete exclusion accounting, and sensitivity analyses are not reported in the registry record. For caffeine, the adjustment for predose concentration adds a modeling step that depends on the estimated individual elimination rate.

Further limitations include the absence of a reported sample-size justification, a full statistical analysis plan, and a stated multiplicity strategy. The record lists many outcomes and analyses but does not explain how conclusions across them were to be controlled or prioritized. Detailed participant characteristics and complete adverse-event descriptions are also not reported in the registry record. These gaps constrain both reproducibility and the scope of interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study in Subjects With Rheumatoid Arthritis to Evaluate the Effect of a Single Dose of Olokizumab on the Pharmacokinetics of Substrates for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 — NCT04246762.
• Registry record last updated 2024-08-15; status last verified 2024-03.
• Results first posted 2024-08-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04246762 is recorded as a completed Phase 1, open-label, single-group study in subjects with rheumatoid arthritis, with enrollment of 17. The study examined pharmacokinetics of CYP450 probe substrates in relation to a single subcutaneous dose of olokizumab 128 mg. The primary outcome was AUC(0-inf) for caffeine, omeprazole, and midazolam, summarized using geometric least-squares means and 95% confidence intervals.

The registry record describes concentration sampling, AUC calculation, and rules for handling predose concentrations and extrapolated AUC. It lists 13 outcome measures and eight analyses. It reports 0 participants with serious adverse events, 6 with other adverse events, and 0 deaths in the listed group. Numerical primary outcome estimates, the complete statistical analysis plan, and sample-size justification are not reported in the registry record.