This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study of Tocilizumab in Combination With an Oral Contraceptive in Patients With Rheumatoid Arthritis (NCT01044498), a randomized phase 3 study. The primary outcome is Serum Progesterone Level.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01044498 |
| Phase | Phase 3 |
| Condition | Rheumatoid Arthritis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 46 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Hoffmann-La Roche |
| Results posted | Yes |
2. Clinical Question
Population
Women with active rheumatoid arthritis received the oral contraceptive in combination with tocilizumab. The study also included healthy female volunteers of child-bearing age who received the oral contraceptive alone. The registry describes the rheumatoid arthritis participants as the population of interest for the interaction assessment.
Intervention
The intervention for the rheumatoid arthritis group was tocilizumab 8 mg/kg as an intravenous infusion on the first day of Cycle 2, while participants received Ortho-Novum® 1/35 daily on Days 1-21 of three consecutive 28-day cycles.
Comparator
The comparison group consisted of healthy volunteers who received Ortho-Novum® 1/35 daily on Days 1-21 of one 28-day cycle. This differs from the rheumatoid arthritis group in both health status and study treatment, so the groups do not represent a simple randomized comparison of tocilizumab versus no tocilizumab among patients with rheumatoid arthritis.
Primary question
The study asked how tocilizumab affected oral-contraceptive pharmacokinetics and pharmacodynamics in women with active rheumatoid arthritis. The listed primary endpoint was serum progesterone measured on Day 21 at specified cycles. Numerical primary-endpoint results and a single comparison are not reported in the registry record.
3. Trial Design
This Phase 3 study is described as open-label, randomized, multi-center, and a one-sequence cross-over drug-interaction study. The registry record also identifies its model as parallel. These descriptions are not fully reconciled in the record, and further detail about the sequence or the meaning of the parallel-model designation is not reported in the registry record.
The listed enrollment was 46. The arm descriptions identify 23 participants in the tocilizumab-plus-oral-contraceptive group and 23 healthy volunteers in the oral-contraceptive group. The rheumatoid arthritis group took Ortho-Novum® 1/35 on Days 1-21 across three consecutive 28-day cycles. Tocilizumab 8 mg/kg was infused on the first day of Cycle 2. Healthy volunteers took the oral contraceptive on Days 1-21 of one 28-day cycle.
The trial began in 2009-12, reached primary completion in 2012-02, and is listed as completed. Masking was none. Thus participants and study personnel were not blinded according to the registry designation. Whether outcome assessors or laboratory personnel were blinded is not reported in the registry record.
The intervention structure is suited to assessing changes in drug exposure and related pharmacodynamic measures around tocilizumab administration in the rheumatoid arthritis group. However, the healthy-volunteer group is not a matching untreated rheumatoid arthritis group. Differences between groups therefore cannot be attributed solely to tocilizumab. The registry record does not report the detailed randomization procedure, allocation concealment, or a statistical plan for comparing the groups.
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.
Overall Study
| Stage | Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Ortho-Novum® 1/35 (Group 2) |
|---|---|---|
| STARTED | 23 | 23 |
| COMPLETED | 20 | 21 |
| NOT COMPLETED | 3 | 2 |
Reasons for not completing this period:
| Reason | Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Ortho-Novum® 1/35 (Group 2) |
|---|---|---|
| Withdrew consent | 1 | 1 |
| Adverse Event | 1 | 1 |
| Other | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading. Blood samples were not available for all patients at all time points.
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.
| Characteristic | Unit | Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Ortho-Novum® 1/35 (Group 2) | Total |
|---|---|---|---|---|
| Participants analysed | 23 | 23 | 46 | |
| Age Continuous | years | 35.8 (SD 7.66) | 25.7 (SD 5.04) | 30.7 (SD 8.22) |
| Sex: Female, Male: Female | Participants | 23 | 23 | 46 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Serum Progesterone Level, measured over Day 21 of Cycles 1-3 for Group 1 and Day 21 of Cycle 1 for Group 2.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | ng/mL |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was serum progesterone level, reported as a mean with standard deviation and measured in ng/mL. Blood samples were collected before administration of Ortho-Novum® 1/35 on Day 21 of each cycle for the rheumatoid arthritis group, and on Day 21 of Cycle 1 for the healthy-volunteer group. The assay used the ADVIA Centaur and ADVIA Centaur XP systems and a competitive immunoassay with direct chemiluminescent technology.
Progesterone is a pharmacodynamic measure in this drug-interaction context: it provides information about a biological response associated with the oral contraceptive. The endpoint can therefore complement pharmacokinetic measures, which describe drug concentrations over time. It is important to distinguish these kinds of measurements: a concentration profile describes exposure, while progesterone is a measured biological outcome.
The registry record states that the primary outcome includes several categories or time points and is not reduced to one comparison. Numerical values for the progesterone endpoint, including means and standard deviations at the specified time points, are not reported in the registry record. Consequently, the direction, magnitude, and precision of any change in progesterone cannot be assessed from this record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the primary endpoint and its measurement schedule but does not report the endpoint values. It therefore does not permit a quantitative estimate of the progesterone response, a comparison between cycles, or an assessment of the precision of such comparisons. In particular, there is no reported effect estimate or confidence interval for the primary outcome. A confidence interval, in general, expresses the range of effects compatible with the data under a stated statistical procedure; without one, the uncertainty around an estimated primary effect cannot be evaluated.
The trial’s structure also matters when interpreting comparisons. Participants with rheumatoid arthritis received both the oral contraceptive and tocilizumab, while healthy volunteers received the oral contraceptive alone. Those groups differ by both disease status and treatment regimen. Any raw difference between them would not isolate the effect of tocilizumab. The registry record does not report an adjusted comparison or other analysis designed to separate those influences.
The adverse-event record reports serious adverse events affecting 1 participant in the tocilizumab-plus-oral-contraceptive group and 0 in the oral-contraceptive group. Other adverse events affected 12 and 4 participants, respectively. These are descriptive counts from the record, not a basis for concluding that one regimen caused more or fewer events. The registry does not report enough detail to assess event timing, duration, severity beyond the serious-event classification, or the statistical uncertainty of group differences. Death counts are not reported in the registry record.
The registry lists pharmacokinetic outcomes for ethinyl estradiol and norethindrone, including maximum concentration, time to maximum concentration, area under the concentration-time curve, terminal half-life, and apparent oral clearance. It also lists pharmacokinetic outcomes for tocilizumab. Numerical results for these measures are not reported in the registry record. The listed outcomes indicate what the study set out to measure; they do not, by themselves, establish the size or direction of any drug interaction.
Overall, the posted record describes the design and planned measurements more fully than the results. It supports a description of what was assessed and who received each regimen, but not a numerical conclusion about progesterone or drug exposure. Any interpretation of an effect, including its clinical importance, would require results and analysis details not reported in the registry record.
9. Statistical Methods Explained
The primary endpoint is a continuous measurement: serum progesterone in ng/mL. The registry says that results were intended to be summarized as a mean and standard deviation. In general, a mean describes the center of a set of measurements, while a standard deviation describes how spread out individual measurements are around that mean. These summaries do not show the full distribution, and neither is reported numerically for the primary outcome in the registry record.
What does a time-point comparison represent?
The measurement schedule includes Day 21 of Cycles 1-3 for the rheumatoid arthritis group and Day 21 of Cycle 1 for healthy volunteers. These are repeated measurements for the rheumatoid arthritis group, rather than separate independent groups at every time point. In general, repeated measurements on the same participant are often correlated: a participant’s values can be more similar to one another than to values from another participant. An analysis that accounts for this dependence can differ from one that treats each measurement as independent. The statistical method used for the primary endpoint is not reported in the registry record.
The record notes that blood samples were not available for all participants at all time points. This means the number of observed measurements may vary across time points. In general, missing observations can affect both the precision and the validity of an estimate, depending on why measurements are missing and how the analysis handles them. The reasons for missing blood samples, the amount of missingness by time point, and the handling of missing measurements are not reported in the registry record.
What do pharmacokinetic measures describe?
The listed outcomes include maximum observed plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) for ethinyl estradiol and norethindrone. In general, Cmax describes the highest observed concentration in a sampling interval, Tmax describes when that peak was reached, and an area-under-the-curve measure summarizes concentration over time. The registry also lists terminal half-life and apparent oral clearance. These measures address different features of drug disposition and should not be treated as interchangeable.
For tocilizumab, the record lists maximum observed serum concentration, time to maximum serum concentration, and area under the serum concentration-time curve from 0 to infinity. The registry record does not report numerical results for these pharmacokinetic outcomes. Nor does it report the sampling schedule or analysis methods used to estimate them. Without those details and results, the size and precision of the exposure estimates cannot be evaluated.
How should uncertainty be understood?
In general, a confidence interval describes the uncertainty around an estimate and indicates which effect values are reasonably compatible with the data under the chosen method. A p-value, when reported, measures the compatibility of the data with a specified null model; it is not a measure of effect size or clinical importance. The registry record does not report a primary-endpoint estimate, confidence interval, or p-value. It also does not report a statistical analysis plan, model specification, or whether analyses were adjusted for baseline values or other variables.
For drug-interaction studies, comparisons of exposure are often expressed using transformed measurements or ratios, but the approach used for this trial is not reported in the registry record. No transformation, comparison scale, or equivalence criterion should be assumed. The listed outcomes alone do not establish that the investigators used any particular method.
What do the planning assumptions mean?
The registry record describes a sample-size illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It describes the effect to detect as a stated fraction of the observed effect. Such an illustration is a planning calculation, not evidence of observed power and not a substitute for an estimate and its uncertainty. The record does not provide a trial-specific sample-size justification or explain whether these assumptions were used to design the study.
In general, sample-size planning depends on the chosen effect, variability, analysis method, allocation, and error rates. If those assumptions do not align with the actual study or analysis, the calculation may not characterize the precision of the resulting estimates. Any calculated planning values should therefore be read as illustrations rather than observed trial findings. No conclusion about the study’s power can be drawn from the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The primary outcome covers several categories or time points and is not reduced to one comparison in the registry record. When multiple outcomes or time-point comparisons are examined, the chance of at least one apparently unusual result can increase. In general, a prespecified testing strategy can address this issue by defining a primary contrast or using a multiplicity adjustment. The record does not report whether such a strategy was specified or used.
The registry lists 14 outcome measures and 0 analyses. The list includes progesterone, multiple pharmacokinetic measures for the oral-contraceptive components, and pharmacokinetic measures for tocilizumab. The absence of listed analyses does not establish that no analyses were conducted; their methods and results are not reported in the registry record. There is no reported hierarchy of outcomes, adjustment method, or distinction between confirmatory and exploratory analyses.
The pharmacokinetic and pharmacodynamic population is defined as enrolled participants with at least 1 evaluable PK or PD sample reading. The record also notes that blood samples were not available for all participants at all time points. It does not give the number of evaluable measurements for each outcome or explain how missing values were handled. In general, results based on available measurements can be affected when missingness is related to participant characteristics or outcomes; the reasons for missing samples are not reported.
The registry record does not describe an intention-to-treat analysis, a per-protocol analysis, imputation, or sensitivity analyses. It also does not provide a detailed accounting of participants contributing to each endpoint. Those omissions limit assessment of how analysis populations and missing data might influence the reported results.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | 1 | 23 | 4.3% |
| Ortho-Novum® 1/35 (Group 2) | 0 | 23 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | 12 of 23 |
| Ortho-Novum® 1/35 (Group 2) | 4 of 23 |
Most frequent serious adverse event terms
| Event term | Organ system | Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Ortho-Novum® 1/35 (Group 2) |
|---|---|---|---|
| Hypersensitivity | Immune system disorders | 1 of 23 | 0 of 23 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Ortho-Novum® 1/35 (Group 2) |
|---|---|---|---|
| Vomiting | Gastrointestinal disorders | 2 of 23 | 3 of 23 |
| Nausea | Gastrointestinal disorders | 2 of 23 | 2 of 23 |
| Headache | Nervous system disorders | 3 of 23 | 0 of 23 |
| Neutropenia | Blood and lymphatic system disorders | 3 of 23 | 0 of 23 |
| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders | 2 of 23 | 0 of 23 |
| Sinus congestion | Respiratory, thoracic and mediastinal disorders | 2 of 23 | 0 of 23 |
| Upper respiratory tract infection | Infections and infestations | 2 of 23 | 0 of 23 |
| LFT abnormal | Investigations | 2 of 23 | 0 of 23 |
| Systolic hypertension | Vascular disorders | 2 of 23 | 0 of 23 |
Serious events with the highest arm-level rate: hypersensitivity (4.3%).
The registry lists serious adverse events affecting 1 participant in the tocilizumab 8 mg/kg plus Ortho-Novum® 1/35 group and 0 participants in the Ortho-Novum® 1/35 group. It lists other adverse events affecting 12 participants and 4 participants, respectively. These figures are counts of participants affected as recorded, not event rates calculated for a follow-up period. The record does not report the timing or duration of the events in these figures.
Hypersensitivity is listed as the top serious term, with 4.3% recorded. The registry does not identify the group association for this term in the information available for this summary, so it should not be assigned to one group. Death counts are not reported in the registry record; a missing value should not be read as evidence that there were no deaths.
These safety counts are descriptive. They do not establish that either regimen caused an event, nor do they provide a precise estimate of comparative risk. The registry record does not report statistical comparisons, confidence intervals, or detailed event-level context. Differences in group characteristics and treatment exposure also limit a direct causal comparison between the rheumatoid arthritis participants and healthy volunteers.
12. What the Result Does, and Does Not, Mean
This trial addresses a focused statistical question: how tocilizumab exposure in women with active rheumatoid arthritis relates to measurements of oral-contraceptive pharmacokinetics and pharmacodynamics. Its outcome list includes serum progesterone as the primary endpoint and concentration-based measures for ethinyl estradiol, norethindrone, and tocilizumab. This combination of measurements reflects distinct parts of a drug-interaction assessment: concentration profiles and a biological response measure.
The record does not report numerical values for the primary progesterone endpoint or the listed pharmacokinetic outcomes. As a result, the magnitude and direction of changes, and the precision of any estimated differences, cannot be determined from the registry record. The record also does not state a primary comparison or describe a statistical model that would clarify how repeated measurements were analyzed.
The healthy-volunteer group provides a descriptive reference for oral-contraceptive measurements without tocilizumab, but it is not a randomized untreated group of participants with rheumatoid arthritis. Disease status and treatment regimen differ between the groups. Thus, a simple contrast between them would not isolate the effect of tocilizumab. The registry record does not report an analysis that resolves this limitation.
The safety counts provide a limited description of adverse events in the recorded groups. They are not proof of causation and do not establish a comparative safety effect. The missing death values and lack of event-level detail further restrict interpretation.
In general, statistical evidence is strongest when a prespecified contrast, an effect estimate, an uncertainty interval, and a clearly described analysis population are available. Those elements are not reported for the primary endpoint in the registry record. The study’s design and outcome list can be described, but the posted information does not support a quantitative conclusion about the size or certainty of the interaction it set out to investigate.
13. Why This Trial Matters Statistically
Drug-interaction studies often need to distinguish pharmacokinetics from pharmacodynamics. Pharmacokinetic outcomes describe concentration and exposure, while pharmacodynamic outcomes describe a biological response. This study’s registry record includes both types: measures of ethinyl estradiol, norethindrone, and tocilizumab concentrations, and serum progesterone. Considering both can be statistically informative because a change in exposure and a change in a biological measure are not the same finding.
The design also illustrates why the comparator matters. The rheumatoid arthritis group received tocilizumab and an oral contraceptive, while healthy volunteers received the oral contraceptive alone. Because the populations differ as well as the regimens, group contrasts are not automatically interpretable as treatment effects. A statistical analysis must match the question and the design, and the analysis details are not reported in the registry record.
Repeated measurements introduce additional considerations. Measurements within a participant may be correlated, and some blood samples were not available at every time point. In general, both features can affect standard errors and the interpretation of comparisons. The registry record does not report how repeated observations or missing measurements were addressed.
Finally, a long outcome list and multiple time points raise questions about which comparisons were primary and how multiplicity was handled. The record does not report a testing strategy or numerical results for the primary endpoint. This makes the trial statistically useful as an example of the importance of complete reporting: design descriptions and outcome names identify the study’s aims, but estimates and uncertainty are needed to assess what the data show.
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 main limitation for interpreting the primary result is that numerical progesterone values are not reported in the registry record. The record identifies the endpoint, summary measure, assay, and collection schedule, but not the estimates or their uncertainty. It therefore does not support assessment of the magnitude, direction, or precision of the primary finding.
The trial’s group structure complicates a direct comparison. Participants with rheumatoid arthritis received tocilizumab with the oral contraceptive, while healthy volunteers received the oral contraceptive alone. Differences between groups could reflect health status, treatment, or both. The record does not report an analysis that separates these factors.
The registry describes the study as a one-sequence cross-over study and also identifies a parallel model. It does not explain this combination of design labels. The randomization method, allocation concealment, detailed sequence, and any washout provisions are not reported in the registry record. The record also does not state whether outcome assessors were blinded.
Blood samples were not available for all participants at all time points, but the reasons, counts by time point, and missing-data methods are not reported. The statistical model for repeated measurements and any adjustment for baseline values are also not reported. These omissions limit evaluation of bias and precision.
Finally, numerical results for the listed pharmacokinetic outcomes are not reported, and the primary outcome is not reduced to one comparison. The record does not describe multiplicity handling or a trial-specific sample-size justification. These gaps prevent a complete statistical assessment even though the study’s objective and measurement plan are described.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Tocilizumab in Combination With an Oral Contraceptive in Patients With Rheumatoid Arthritis — NCT01044498.
- Registry record last updated 2013-04-01; status last verified 2013-03.
- Results first posted 2013-03-12.
- 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.
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18. Record Summary
NCT01044498 is a completed Phase 3, randomized, open-label study sponsored by Hoffmann-La Roche. It began in 2009-12, reached primary completion in 2012-02, and lists enrollment of 46. The study examined tocilizumab with Ortho-Novum® 1/35 in women with active rheumatoid arthritis and oral-contraceptive use alone in healthy female volunteers.
The primary endpoint was serum progesterone measured on Day 21 at specified cycles. The registry also lists pharmacokinetic outcomes for ethinyl estradiol, norethindrone, and tocilizumab. Numerical results for the primary endpoint and these pharmacokinetic measures are not reported in the registry record. Serious adverse events affected 1 participant in the tocilizumab-plus-oral-contraceptive group and 0 in the oral-contraceptive group; death counts are not reported.
The registry describes a one-sequence cross-over study while also listing a parallel model. It does not report enough analysis detail or endpoint results to resolve that design description or quantify the primary finding.