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 DMARD Therapy in Patients With Active Rheumatoid Arthritis. (NCT00773461), a randomized phase 3 study. The primary outcome is Percentage of Participants With an American College of Rheumatology (ACR)20 Response at Week 24.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00773461 |
| Phase | Phase 3 |
| Condition | Rheumatoid Arthritis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 209 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Hoffmann-La Roche |
| Results posted | Yes |
2. Clinical Question
Population
Participants had active rheumatoid arthritis and an inadequate response to current DMARD therapy. The primary endpoint specifies the ITT Population. Enrollment was 209 participants.
Intervention
The intervention was tocilizumab, identified as RoActemra/Actemra, given intravenously at 8mg/kg every 4 weeks with stable DMARD therapy. The brief summary describes randomization in a 2:1 ratio.
Comparator
The comparator was intravenous placebo every 4 weeks, also alongside stable DMARD therapy. The registry record identifies placebo plus DMARDs and tocilizumab plus DMARDs as the treatment groups.
Primary question
The primary endpoint asks what percentage of participants in the ITT Population achieved an ACR20 response at Week 24. A response required at least a 20% improvement from baseline in both tender and swollen joint counts, plus improvement in 3 out of 5 additional ACR core set variables. The registry record does not report a single comparison of the response percentages between groups.
3. Trial Design
This was a randomized, double-blind, parallel-group phase 3 trial, with tocilizumab and placebo each given in combination with DMARD therapy. The trial enrolled 209 participants and is listed as completed. The sponsor was Hoffmann-La Roche. The registry record lists the study start as 2008-10-31 and primary completion as 2010-07-22.
The brief summary describes assignment in a 2:1 ratio to tocilizumab 8mg/kg intravenously or placebo intravenously every 4 weeks. Both groups continued stable DMARD therapy. The anticipated time on study treatment was 3-12 months, and the stated target sample size was 100-500 individuals. These are descriptions of the plan; the registry record does not give arm-specific enrollment figures in the trial details stated.
Randomization assigns participants to treatment groups by chance. In general, this can reduce systematic differences between groups at baseline, though it does not guarantee identical groups. Double masking means that treatment assignment was concealed from more than one party, but the registry record does not specify which parties were masked or how masking was maintained. The parallel-group structure means that the assigned groups were followed as separate groups rather than participants switching through a sequence of treatments.
The record lists several secondary outcomes, including ACR50 and ACR70 responses, escape therapy, joint counts, global assessments, pain, C-reactive protein, and ESR at Week 24. It lists 17 outcome measures and 15 analyses. Details of the analysis plan beyond the endpoint description 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.
Overall Study
| Stage | Placebo + DMARDs | Tocilizumab + DMARDs |
|---|---|---|
| STARTED | 70 | 139 |
| COMPLETED | 65 | 135 |
| NOT COMPLETED | 5 | 4 |
Reasons for not completing this period:
| Reason | Placebo + DMARDs | Tocilizumab + DMARDs |
|---|---|---|
| Adverse Event | 1 | 3 |
| Withdrawal by Subject | 4 | 1 |
Analysis population for the primary outcome, as defined in the registry: ITT Population
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: Intent-to-Treat (ITT) Population: The ITT population included all randomized participants who received at least one infusion of study treatment; Per Protocol (PP) Population: The PP population included all participants in the ITT population who adhered to the protocol.
| Characteristic | Unit | Placebo + DMARDs | Tocilizumab + DMARDs | Total |
|---|---|---|---|---|
| Participants analysed | 69 | 139 | 208 | |
| Age, Continuous | years | 47.8 (SD 11.68) | 46.8 (SD 11.01) | 47.1 (SD 11.22) |
| Sex: Female, Male: Female | Participants | 55 | 120 | 175 |
| Sex: Female, Male: Male | Participants | 14 | 19 | 33 |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of Participants With an American College of Rheumatology (ACR)20 Response at Week 24, measured over Week 24.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Percentage of Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the percentage of participants in the ITT Population with an ACR20 response at Week 24. ACR20 is a categorical response measure: a participant either meets the specified response criteria or does not. The measure requires at least a 20% improvement from baseline in both tender joint count and swollen joint count, together with improvement in 3 out of 5 additional core set variables: physician’s global assessment of disease activity, participant’s global assessment of disease activity, participant’s assessment of pain, HAQ-DI, and C-reactive protein.
This endpoint combines joint findings with assessments of disease activity, pain, function, and an inflammatory marker. In general, combining measures can describe response across more than one aspect of a condition, while the threshold makes the outcome interpretable as the proportion meeting a defined response criterion. It does not describe the size of improvement among participants who respond, or the distribution of changes among those who do not meet the threshold.
The registry record says CRP was used primarily in calculating the ACR response and that ESR was substituted if CRP was missing. It also mentions an ITT sensitivity analysis using last observation carried forward. Arm-specific response counts or percentages and a single between-group result are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a relevant comparison: tocilizumab plus DMARD therapy versus placebo plus DMARD therapy, with ACR20 response at Week 24 as the primary endpoint. However, it does not provide a single arm-level comparison for that endpoint. Response counts or percentages by group, an estimated difference between groups, a confidence interval, and a p value are not reported in the registry record. The treatment contrast therefore cannot be quantified from the endpoint information stated.
The endpoint definition is detailed enough to explain what counted as a response, but a definition is not a result. It specifies the joint-count threshold and the additional variables required; it does not say how many participants met the criteria in either group. The same distinction applies to the ITT designation: it names the population for the primary endpoint, but does not supply the analysis result or explain all participant-level rules used to form that population.
The record does include adverse-event counts. For serious adverse events, it lists 4 affected participants among 68 at risk in the placebo plus DMARDs group and 1 among 139 at risk in the tocilizumab plus DMARDs group. For other adverse events, it lists 19 among 68 and 59 among 139, respectively. These are descriptive counts, not a substitute for the missing primary endpoint comparison. They also do not establish why the events occurred or provide a complete assessment of the balance of benefits and harms.
In general, a confidence interval describes the range of effect sizes compatible with the data under the analysis assumptions. Without the endpoint estimate and its uncertainty interval, readers cannot assess how precise the primary comparison is or which effect sizes remain compatible with the posted results. A p value is also not a measure of effect size or clinical importance. No primary endpoint p value is reported in the registry record.
The information supports describing the trial’s design, its planned endpoint, and the posted adverse-event counts. It does not support a numerical conclusion about the primary treatment contrast. Missing endpoint results should not be interpreted as evidence that the groups had the same response, nor as evidence of a particular difference.
9. Statistical Methods Explained
The primary outcome is a percentage, so each participant is classified according to whether the ACR20 response criteria were met. In general, this is a binary outcome: each participant contributes to the response or non-response category. A group percentage expresses the share of participants who met the criteria, but it does not show the range of individual changes that produced those classifications. The registry record names the outcome and its criteria but does not report the group response values.
What does randomization contribute?
Randomization assigns participants to treatment groups by chance. In general, this helps limit systematic selection differences between groups and supports a comparison of outcomes according to assigned treatment. Randomization does not prevent all imbalance, guarantee that every relevant characteristic is matched, or eliminate the need to describe the analysis population and missing data. The record states that the study was randomized but does not report the sequence-generation method, concealment procedure, or baseline balance details.
The study is described as double blind and parallel. In general, masking can reduce the influence of treatment expectations on participant reports, clinical assessments, or other trial processes. The specific people masked and the procedures used are not reported in the registry record. A parallel design compares separate groups assigned to the respective treatments; the registry does not report further details of follow-up or adherence in the information used for this explanation.
What does the ITT label mean?
The primary endpoint names the ITT Population. In general, intention-to-treat analysis is intended to retain participants in the groups to which they were randomized, so that the comparison reflects assignment rather than only treatment received. The term alone does not reveal how this trial handled participants with missing endpoint information, protocol deviations, or discontinuation. Those specific details are not reported in the registry record.
How should the response definition be read?
ACR20 is based on a threshold rather than a continuous average change. A participant had to meet at least a 20% improvement from baseline in both tender and swollen joint counts and improvement in 3 out of 5 additional variables. The listed variables cover physician and participant global assessments of disease activity, participant assessment of pain, HAQ-DI, and CRP. The registry says ESR was substituted when CRP was missing. This substitution is part of the stated endpoint definition; additional rules for other missing components are not reported.
Turning measurements into a response category can make a result easier to describe as the proportion reaching a defined level of improvement. In general, however, a threshold discards information about the exact magnitude of change and can place participants with similar changes on different sides of a cutoff. A binary response percentage should therefore be interpreted as the frequency of meeting the specified criteria, not as a complete account of symptom or measurement changes.
What can uncertainty measures tell readers?
In general, a confidence interval around a group contrast communicates statistical uncertainty by indicating a range of values compatible with the data and the analysis assumptions. The width depends on features such as the amount of information in the data and the variability of the outcome. A p value addresses compatibility with a specified null hypothesis under an analysis model; it does not measure the probability that the null hypothesis is true, nor does it quantify the size or importance of an effect. The registry record does not report a primary endpoint estimate, confidence interval, or p value, so no precision assessment or significance interpretation is possible for that endpoint.
What do the planning assumptions describe?
The registry’s sample-size assumptions describe a planning illustration computed from the observed effect, not the trial’s own design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. Such an illustration is a planning calculation, not observed power and not evidence about the trial’s actual design justification. The record does not report the trial’s sample-size justification. No numerical planning results for this endpoint are stated in the registry record.
In general, over-dispersion matters when observed variability is greater than a model expects: standard errors can be too small if the extra variability is ignored. That issue is particularly relevant to some count outcomes, but the primary endpoint in this trial is a participant percentage. The record does not report a dispersion parameter or a model for the primary endpoint, so it is not possible to say whether or how such a concern entered the sponsor’s analysis.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 17 outcome measures and 15 analyses, including the primary ACR20 response and outcomes such as ACR50 and ACR70, escape therapy, joint counts, global assessments, pain, CRP, and ESR. Having multiple outcomes creates a general multiplicity issue: when many hypotheses are assessed, the chance of at least one apparently unusual finding can increase if no adjustment or testing hierarchy is used. The registry record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a complete statistical analysis plan. It is therefore not possible to determine how multiplicity was handled.
The primary endpoint description states that CRP was used primarily in calculating ACR response, with ESR substituted if CRP was missing. It also states that an ITT sensitivity analysis used last observation carried forward (LOCF). In general, LOCF fills a missing later measurement with an earlier observed value. This makes assumptions about what would have happened after the last observation; it does not remove uncertainty about missing outcomes. The registry record does not report the amount or pattern of missing primary endpoint data, the main analysis’s missing-data method, or the detailed LOCF implementation.
The primary endpoint names the ITT Population, but the participant-level definition and handling of deviations are not reported. The record does not give the primary response counts, arm-specific percentages, uncertainty intervals, or p value. It also does not state whether other sensitivity analyses were conducted. These gaps limit assessment of robustness and leave the multiplicity and missing-data implications unclear.
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 |
|---|---|---|---|
| Placebo + DMARDs | 4 | 68 | 5.9% |
| Tocilizumab + DMARDs | 1 | 139 | 0.7% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Placebo + DMARDs | 19 of 68 |
| Tocilizumab + DMARDs | 59 of 139 |
Most frequent serious adverse event terms
| Event term | Organ system | Placebo + DMARDs | Tocilizumab + DMARDs |
|---|---|---|---|
| Abscess Limb | Infections and infestations | 1 of 68 | 0 of 139 |
| Herpes Zoster | Infections and infestations | 1 of 68 | 0 of 139 |
| Uterine Infection | Infections and infestations | 1 of 68 | 0 of 139 |
| Pyrexia | General disorders | 1 of 68 | 0 of 139 |
| Neutrophil Count Decreased | Investigations | 0 of 68 | 1 of 139 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Placebo + DMARDs | Tocilizumab + DMARDs |
|---|---|---|---|
| Upper respiratory tract infection | Infections and infestations | 4 of 68 | 9 of 139 |
| Alanine aminotransferase increased | Investigations | 1 of 68 | 8 of 139 |
| Leukopenia | Blood and lymphatic system disorders | 0 of 68 | 9 of 139 |
| Nasopharyngitis | Infections and infestations | 1 of 68 | 6 of 139 |
| Rash | Skin and subcutaneous tissue disorders | 1 of 68 | 4 of 139 |
| Influenza | Infections and infestations | 3 of 68 | 1 of 139 |
| Neutrophil count decreased | Investigations | 1 of 68 | 3 of 139 |
| White blood cell count decreased | Investigations | 0 of 68 | 4 of 139 |
| Pyrexia | General disorders | 2 of 68 | 2 of 139 |
| Aspartate aminotransferase increased | Investigations | 0 of 68 | 3 of 139 |
Serious events with the highest arm-level rate: abscess limb (1.5%), herpes zoster (1.5%), uterine infection (1.5%), pyrexia (1.5%), neutrophil count decreased (0.7%).
The registry lists serious adverse events for 4 participants among 68 at risk in the placebo plus DMARDs group and 1 participant among 139 at risk in the tocilizumab plus DMARDs group. For other adverse events, it lists 19 participants among 68 at risk and 59 among 139 at risk, respectively. These figures describe participants recorded as affected; they do not by themselves establish causation or indicate the severity of every non-serious event.
The listed serious-event terms include Abscess Limb, Herpes Zoster, Uterine Infection, and Pyrexia, each reported as 1.5%, and Neutrophil Count Decreased, reported as 0.7%. The registry record does not provide further detail about these terms in the information. Death counts are not reported in the registry record; that absence should not be read as confirmation that no deaths occurred.
In general, adverse-event counts are best read alongside the group sizes, definitions, follow-up, and completeness of reporting. The registry record does not state the event-attribution rules, exposure-adjusted rates, or a statistical comparison for these safety figures. They are descriptive and should not be treated as a stand-alone causal comparison.
12. What the Result Does, and Does Not, Mean
The record establishes the basic clinical and statistical question: among participants with active rheumatoid arthritis and an inadequate response to current DMARD therapy, how did ACR20 response at Week 24 compare between tocilizumab plus DMARD therapy and placebo plus DMARD therapy? It also defines the response rule and identifies the ITT Population. These details make the intended endpoint understandable.
What the record does not report is the primary result needed to answer that question numerically. There are no group-specific ACR20 response percentages or counts, no estimated between-group contrast, and no confidence interval or p value in the information stated. The missing comparison does not mean the groups were equal, and it does not imply that one group had a higher response. It means the primary treatment contrast cannot be judged from these registry entries.
The safety counts provide descriptive information about participants with recorded adverse events in each group. They do not establish that treatment caused an event, explain differences between groups, or replace the primary efficacy outcome. The serious adverse event term percentages are listed, but more detailed event descriptions and a complete account of safety analyses are not reported in the registry record.
In general, statistical evidence should be interpreted using both an estimate of the effect and its uncertainty, with attention to the outcome definition, analysis population, missing data, and multiplicity. Without the primary estimate and uncertainty, readers cannot assess the magnitude, precision, or compatibility of the data with different possible treatment effects. The registry information supports a description of the study and its outcomes, but not a conclusion about the direction or size of the primary comparison.
13. Why This Trial Matters Statistically
This trial illustrates why a clearly defined endpoint and a reported treatment contrast are both necessary for statistical interpretation. ACR20 is described through joint-count thresholds and additional core set variables, so the response criterion is explicit. Yet without the response numbers for each group and an estimate of their contrast, the primary question remains unanswered by the registry entries. A precise endpoint definition is not a substitute for a result.
The study also shows how several sources of information fit together. Randomization and double masking describe important design features; the ITT label describes the named primary population; the endpoint description specifies how response was classified; and the safety counts provide a separate descriptive view. In general, each component answers a different question. None can stand in for an unreported primary estimate, and no single design feature guarantees that an analysis is unbiased or precise.
Reporting the missing-data approach and multiplicity plan matters because the primary outcome depends on several measurements and the record lists multiple outcomes. The stated CRP-to-ESR substitution and LOCF sensitivity analysis offer some information about handling missing values, but the broader details are not reported. This limits the ability to assess how robust any primary result would be to alternative assumptions.
For clinical researchers and biostatisticians, the record is a useful reminder to distinguish trial design, outcome definition, analysis population, and observed results. A trial can be completed and have a specified primary endpoint while still lacking the result details needed to evaluate effect size and precision from the registry record.
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 principal limitation for interpreting efficacy is that the registry record does not report arm-specific ACR20 response results or a single between-group estimate. Without those values, readers cannot evaluate the magnitude or precision of the primary contrast. The record also does not report a primary endpoint confidence interval or p value.
Although the endpoint description identifies the ITT Population and an LOCF sensitivity analysis, the participant-level definition of the analysis population and the main missing-data method are not reported. The record does not give the extent or pattern of missing outcome measurements, nor detailed procedures for applying the CRP-to-ESR substitution across the endpoint variables.
The record lists 17 outcome measures and 15 analyses, but does not state a testing hierarchy or multiplicity adjustment. It also does not report a complete statistical analysis plan, the trial’s sample-size justification, or numerical assumptions used in that justification. A separate planning illustration is not the same as the original design rationale.
For safety, the record provides counts and selected serious-event terms, but does not report a statistical comparison, exposure-adjusted rates, event-attribution rules, or further detail about the listed terms. Death counts are not reported in the registry record. These limitations constrain interpretation of both efficacy and safety and should not be replaced by assumptions about unreported procedures or results.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Tocilizumab in Combination With DMARD Therapy in Patients With Active Rheumatoid Arthritis. — NCT00773461.
- Registry record last updated 2017-08-01; status last verified 2017-06.
- Results first posted 2016-07-21.
- 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
The registry record describes a completed randomized, double-blind, parallel-group phase 3 study sponsored by Hoffmann-La Roche. It enrolled 209 participants with active rheumatoid arthritis and an inadequate response to current DMARD therapy. The comparison was tocilizumab plus DMARDs versus placebo plus DMARDs.
The primary endpoint was the percentage of the ITT Population with an ACR20 response at Week 24. The response definition required at least a 20% improvement from baseline in both tender and swollen joint counts and improvement in 3 out of 5 additional variables. CRP was used primarily, with ESR substituted if CRP was missing; an ITT sensitivity analysis used LOCF.
Arm-specific primary response results and a single treatment comparison are not reported in the registry record. Adverse-event counts are listed, along with selected serious-event terms. Further details on the analysis plan, multiplicity, missing data, and safety comparisons are not reported.