A Study of CNTO 136 (Sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy (SIRROUND-T): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of CNTO 136 (Sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy (SIRROUND-T) (NCT01606761), a randomized phase 3 study. The primary outcome is Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16.

2. Clinical Question

The central question was whether participants with active rheumatoid arthritis despite anti-TNF-alpha therapy had different Week 16 ACR 20 response rates when assigned to sirukumab or placebo. The registry describes people who were unresponsive or intolerant to anti-TNF-alpha agents. The primary endpoint assessed a combined improvement criterion rather than a single symptom or laboratory result.

The endpoint concerns a threshold response: participants had to meet joint-count improvement criteria and improve on additional assessments. The registry also reports Week 24 outcomes relating to greater clinical response, remission, and physical function. Those measures add context, but they are distinct outcomes assessed at a later time.

3. Trial Design

This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study. The registry reports enrollment of 878 participants. Random allocation and double masking are recorded, but details such as the allocation sequence generation, concealment procedures, and who specifically remained masked are not reported in the registry record.

Participants were assigned to placebo, sirukumab 50 mg, or sirukumab 100 mg. The 50 mg regimen was scheduled every 4 weeks beginning at Week 0. The 100 mg regimen was scheduled every 2 weeks beginning at Week 0. The placebo regimen was given every 2 weeks through Week 22, followed by a sirukumab regimen through Week 52. The record also describes placebo injections between active injections in the 50 mg group.

The primary outcome was assessed at Week 16, before the planned placebo-to-sirukumab transition described for Week 24 onward. The primary population was the efficacy full analysis set, defined in the record as all randomized participants. Arm-level denominators for the posted primary result were 294 for placebo, 292 for sirukumab 50 mg, and 292 for sirukumab 100 mg.

The registry lists a primary completion date of 2015-03-17 and a completed study status. It does not report the original sample-size justification, the intended handling of protocol deviations, detailed inclusion and exclusion criteria, or the full schedule of study visits. The extension of assigned treatment and subsequent changes in treatment mean that results after the placebo-controlled period have a different treatment context from the Week 16 comparison.

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 878 participants (placebo \[n=294\], sirukumab 50 mg every 4 week (q4w) \[n=292\], and sirukumab 100 milligram (mg) every 2 week (q2w) \[n=292\]) were randomized and included in the study.

Prior to Week 24

Reasons for not completing this period:

Week 24 to Week 52

Reasons for not completing this period:

Safety Follow-up Period (Week 52-68)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy full analysis set included all participants who were randomized into the study.

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 Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16, measured over Week 16.

The primary endpoint was the percentage of participants achieving an American College of Rheumatology 20 response at Week 16. The registry defines this as at least 20 percent improvement in both swollen joint count, assessed across 66 joints, and tender joint count, assessed across 68 joints, together with at least 20 percent improvement in 3 of the following 5 assessments: the participant’s pain assessment, the participant’s global assessment of disease activity, the physician’s global assessment of disease activity, physical function measured using the Health Assessment Questionnaire-Disability Index, and serum C-reactive protein.

This composite is used to represent improvement across several aspects of rheumatoid arthritis rather than relying on only one measure. In general, a threshold-based composite classifies each participant as either meeting or not meeting the specified response definition. The resulting group percentage is straightforward to interpret, but it does not show the size of improvement beyond the threshold or how each component changed individually.

The primary endpoint therefore answers a focused question about how often the defined response occurred by Week 16. It does not by itself describe longer-term changes, the full range of symptom change, or the contribution of each component. Component-level results are not reported in the registry record.

7. Results Posted in the Registry

• Sirukumab 50 mg: 40.1% (117/292) versus 24.1% (71/294) on control; risk difference 15.9 percentage points (95% CI 8.5 to 23.4), risk ratio 1.66 (1.30–2.12); unadjusted two-proportion z-test p = <0.001.
• Sirukumab 100 mg: 45.2% (132/292) versus 24.1% (71/294) on control; risk difference 21.1 percentage points (95% CI 13.5 to 28.6), risk ratio 1.87 (1.47–2.38); unadjusted two-proportion z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Sirukumab 50 mg: 20.9% (61/292) versus 8.8% (26/294) on control; risk difference 12.0 percentage points (95% CI 6.4 to 17.7), risk ratio 2.36 (1.54–3.63); unadjusted two-proportion z-test p = <0.001.
  • Sirukumab 100 mg: 21.6% (63/292) versus 8.8% (26/294) on control; risk difference 12.7 percentage points (95% CI 7.0 to 18.5), risk ratio 2.44 (1.59–3.74); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Sirukumab 50 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Sirukumab 100 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Sirukumab 50 mg: 19.2% (56/292) versus 8.2% (24/294) on control; risk difference 11.0 percentage points (95% CI 5.5 to 16.5), risk ratio 2.35 (1.50–3.68); unadjusted two-proportion z-test p = <0.001.
  • Sirukumab 100 mg: 21.6% (63/292) versus 8.2% (24/294) on control; risk difference 13.4 percentage points (95% CI 7.8 to 19.1), risk ratio 2.64 (1.70–4.11); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Sirukumab 50 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Sirukumab 100 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary outcomes follow a consistent broad pattern: both sirukumab groups have higher outcome percentages than placebo at Week 24 across the reported ACR 50 response and DAS28 (CRP) remission measures. The registry also lists change from baseline in HAQ-DI score at Week 24 as a secondary outcome, but a result for that outcome is not reported in the registry record. The available secondary results thus extend the primary endpoint pattern to more demanding response or remission definitions, while leaving the physical-function outcome without a posted result in this record.

This pattern is directionally compatible with the Week 16 primary result, but the secondary endpoints address different criteria and were assessed at a different time. They do not directly validate the primary endpoint, and they do not show that all participants had the same degree or type of improvement. Each is a separate group-level outcome with its own definition and uncertainty.

The registry reports sponsor analyses for the posted binary secondary outcomes, with p < 0.001 for each active-treatment comparison against placebo. However, the record does not report a multiplicity adjustment or a hierarchy governing interpretation of these secondary tests. When multiple outcomes and comparisons are examined, unadjusted p-values carry less confirmatory weight because the chance of at least one apparently strong result can increase across repeated testing. The secondary findings are therefore best treated as supportive rather than as independent proof of a broad pattern across all possible outcomes.

Missing endpoint details also matter for these outcomes. The registry does not state how missing Week 24 values were treated, whether the analysis population was identical for each secondary endpoint, or whether sensitivity analyses were conducted. These results provide useful context, but their interpretation should remain tied to the definitions and analysis details that are actually reported.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24
• Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24
• Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each person either met the ACR 20 response definition at Week 16 or did not. A group percentage expresses the observed frequency of that event. The registry reports both these percentages and comparisons of each sirukumab group with placebo.

What is a percentage difference?

In general, a percentage difference between groups describes the difference in the proportion meeting an outcome. It is expressed in percentage points, not as a relative percentage increase. For the primary comparison, the registry reports percentage differences of 15.9 for sirukumab 50 mg versus placebo and 21.0 for sirukumab 100 mg versus placebo. These are the sponsor’s reported contrast estimates, not a comparison between the two active regimens.

The arm-level outcome percentages and the comparison estimates may not display identical last digits because the sponsor’s analysis used the Cochran-Mantel-Haenszel method, while a simple recalculation from posted summary statistics is unadjusted. The sponsor’s method is the reported analysis. The registry does not describe the strata or adjustment variables used for its Cochran-Mantel-Haenszel analyses, so their specific role cannot be assessed from the record.

What does the Cochran-Mantel-Haenszel method do?

In general, this method estimates an association or treatment contrast across defined strata, while accounting for the stratification structure. It can combine information across strata rather than treating all observations as if no strata existed. The usefulness and interpretation of that adjustment depend on how the strata were defined and on the analysis details. Those details are not reported in the registry record, so the reported method can be named but not fully reconstructed.

How should the p-values be read?

A p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of the analysis. In the registry analyses, both primary comparisons have p < 0.001. This does not measure the probability that the null hypothesis is true, the size or importance of an effect, or the probability that a result will replicate. It also does not account automatically for multiple outcomes or comparisons. The registry does not report whether the primary analysis incorporated a multiplicity adjustment.

The registry’s reported p-values and estimates belong to its own analysis. The recalculated comparisons are simple, unadjusted calculations based on the posted group summaries. They are useful as a check on the direction and approximate scale of the contrast, but do not reproduce the sponsor’s analysis method. No discrepancy is flagged for this trial. The sponsor’s analysis remains the relevant reported analysis.

What does a confidence interval add?

In general, a confidence interval communicates uncertainty about an estimate. A narrower interval indicates greater precision, while a wider interval indicates less precision, given the model and data. A 95% confidence interval is produced by a procedure that, under its assumptions, would cover the target parameter in 95% of repeated applications. It is not a statement that there is a 95% probability that the particular fixed parameter lies within the interval.

For the primary percentage differences, the posted 95% intervals are 8.5 to 23.2 for sirukumab 50 mg versus placebo and 13.6 to 28.5 for sirukumab 100 mg versus placebo. Both intervals are entirely above zero. That is consistent with the reported p-values for a test of no difference, although the interval and p-value do not convey clinical importance on their own. The interval describes uncertainty in the group contrast, not variability among individual participant outcomes.

Why distinguish the primary endpoint from secondary outcomes?

A trial can assess several outcomes, but repeated testing creates more opportunities for a nominally small p-value to occur by chance. In general, multiplicity procedures control or otherwise address that issue by changing the testing strategy or interpretation. The registry lists three secondary outcomes, but does not report a multiplicity strategy. Those results should therefore be read as additional evidence with less confirmatory weight than a result from a clearly specified, multiplicity-controlled testing plan.

The registry’s outcome population is described as all randomized participants in the efficacy full analysis set. That is important because the intended analysis population affects which participants contribute to an estimate. Still, a population definition alone does not explain how missing endpoint measurements, treatment discontinuation, protocol deviations, or intercurrent events were handled. These details are not reported in the registry record.

In general, missing-data assumptions matter because people without observed outcomes may differ from those with observed outcomes. Methods such as imputation, likelihood-based approaches, or explicit sensitivity analyses can make different assumptions, but the registry does not identify which, if any, were used for this endpoint. It is therefore not possible to determine from the posted record whether missingness could change the results.

11. Confidence Intervals and Precision

The sponsor-reported 95% confidence interval for the Week 16 percentage difference between sirukumab 50 mg and placebo extends from 8.5 to 23.2. For sirukumab 100 mg versus placebo, it extends from 13.6 to 28.5. Both intervals lie above zero, and both have p < 0.001 in the reported analyses. The intervals give a sense of the range of contrast estimates compatible with the data and analysis, rather than a precise forecast of what would occur in another study.

The intervals are not especially narrow relative to their point estimates, so there remains uncertainty about the magnitude of each contrast. They are also not so broad as to include zero in these reported analyses. This distinction separates evidence about the direction of the estimated contrast from precision about its size. Statistical compatibility with a positive difference does not, by itself, say whether the size is clinically important.

Confidence intervals describe uncertainty in estimated group-level effects. They do not show the distribution of responses among individuals, and they do not mean that every participant experienced the group-average pattern. The endpoint is a binary threshold response, so its estimate is a proportion and its interval reflects uncertainty about that proportion contrast under the analysis method.

The registry provides intervals for the sponsor’s comparisons and the recalculation also includes intervals derived from posted summaries. The sponsor’s reported intervals are tied to the reported Cochran-Mantel-Haenszel analysis; simple unadjusted recalculations use different methods and assumptions. Differences in the last reported digits should not be mistaken for contradictory findings. The specific stratification details and missing-data procedures are not reported in the registry record, limiting a fuller assessment of precision.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. The illustrations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They use the observed effect as a reference and consider effects at 100%, 75%, and 50% of that observed effect. These are planning assumptions for the illustration; the original trial design assumptions are not reported in the registry record.

The 80% power column indicates the illustrative number of participants per arm for a design that would have an 80% chance of detecting the specified effect under the stated assumptions, if that effect and those assumptions held. The 90% power column expresses the analogous planning target at 90% power. These are design calculations for hypothetical studies, not properties measured from the completed trial.

For each comparison, the rows represent planning for 100%, 75%, or 50% of the observed effect. Smaller effects are harder to distinguish from random variation and therefore require more participants to attain the same target power under the same assumptions. The figures are not observed power, and they should not be interpreted as a retrospective measure of how likely the completed trial was to detect its result.

These calculations also do not reproduce the trial’s original sample-size calculation. The registry does not report the assumptions used to plan enrollment, such as the originally anticipated response rates or target effect. The planning illustrations are consequently best read as sensitivity demonstrations: changing the effect size changes the participant requirement. They do not establish that the original study was planned on these assumptions, nor do they account for any design features not included in the stated illustration.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.241; treatment proportion p₁ = 0.401; average p̄ = 0.321.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6603 = 1.2941.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6506 = 0.5476.
4. n = (1.2941 + 0.5476)² / (0.1592)² = 133.9, rounded up to 134 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.241496598639456                          # control proportion
p1 <- 0.400684931506849                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1606761)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 134 (80% power), 179 (90% power)
 75% of observed effect: n per arm = 231 (80% power), 309 (90% power)
 50% of observed effect: n per arm = 500 (80% power), 669 (90% power)
power.prop.test: 133.9 
Simulated power at n = 134 per arm: 0.801 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparisons using the Cochran-Mantel-Haenszel method. The reported percentage difference was 15.9 for sirukumab 50 mg versus placebo and 21.0 for sirukumab 100 mg versus placebo; each comparison had p < 0.001. The corresponding 95% confidence intervals were 8.5 to 23.2 and 13.6 to 28.5.

The recalculated contrasts are simple unadjusted calculations from posted summary statistics. They are a statistical cross-check, not a replacement for the sponsor’s analysis. The two approaches use different methods, so slight differences in displayed estimates or interval limits can occur. The direction and overall scale of the comparisons are consistent, and no discrepancy is flagged for this record.

The registry does not report the strata or other analysis details needed to reconstruct the sponsor’s Cochran-Mantel-Haenszel calculation. Therefore, the sponsor-reported analysis is the principal inferential result, while the recalculation provides supplementary context about the posted group summaries. The record does not identify whether an adjustment for multiple comparisons was applied to the primary result.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and lists secondary outcomes, but a multiplicity strategy is not reported in the registry record. It is therefore unknown whether the testing sequence, p-values, or confidence intervals were adjusted to account for testing multiple outcomes or treatment comparisons. This matters most for confirmatory interpretation: repeated testing can make nominal results appear stronger than they would under a prespecified family-wise testing plan. The primary findings remain the results the registry reports, but the strength of formal inference across the full set of endpoints cannot be evaluated from the record.

The primary efficacy population is described as all participants randomized into the study. This definition clarifies the intended population, but does not establish how participants without an observed Week 16 outcome were handled. The registry does not report the amount or pattern of missing primary endpoint data, the method used to handle missingness, or sensitivity analyses under alternative assumptions. It also does not state how treatment discontinuation or other post-randomization events affected endpoint classification.

In general, missing-data approaches rely on assumptions about outcomes that were not observed. If the probability of missingness is related to outcome or treatment, estimates may depend on those assumptions. Without information on missing observations and the analysis procedure, the extent of that potential influence cannot be assessed.

The same reporting limitations apply to the Week 24 secondary outcomes. The record does not specify the exact analysis population for each secondary result or the approach to missing measurements. The registry also does not report detailed protocol-deviation handling or an analysis plan sufficient to determine whether reported analyses followed a prespecified hierarchy. These are limits of what can be evaluated from the registry record, not evidence that a particular method was or was not used.

16. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: diverticular perforation (5.3%), erysipelas (5.3%), pneumonia (1.7%), rheumatoid arthritis (1.6%), cellulitis (1.6%).

The adverse-event record separates findings by treatment period and group, so the denominators are not all the same. During Week 24, the placebo group had 15 participants with a serious adverse event among 294 at risk. For the Week 24 to Week 52 transition groups, 8 of 124 participants in the placebo-to-50 mg group and 18 of 126 in the placebo-to-100 mg group had serious adverse events. At Week 52, the reported counts were 51 among 292 for sirukumab 50 mg and 37 among 292 for sirukumab 100 mg.

These figures should be read as counts within the named treatment-period groups, not as a single directly comparable safety contrast. Treatment exposure and follow-up periods differ, and the placebo groups transition to sirukumab in the record. The registry’s listed serious-event terms include diverticular perforation and erysipelas at 5.3% each, pneumonia at 1.7%, rheumatoid arthritis and cellulitis at 1.6% each, and unstable angina at 1.0%. The registry does not report deaths in these posted safety entries. These data alone do not establish causation or allow a full comparative safety assessment.

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

The reported Week 16 results indicate that a larger proportion of participants in each sirukumab group met the registry’s ACR 20 response definition than in the placebo group. The reported percentage differences and confidence intervals describe the size and uncertainty of those group contrasts under the sponsor’s analysis. They do not establish that every participant responded, quantify the experience of any individual, or describe changes in every component of the composite.

The result is specific to participants with active rheumatoid arthritis despite anti-TNF-alpha therapy, the regimens studied, and the Week 16 assessment. It cannot automatically be extended to other populations, dosing schedules, treatment durations, or outcomes. The registry record does not provide the details needed to assess generalizability beyond its stated population and study design.

A statistically strong result is not the same as a complete judgment about clinical importance. The record reports a threshold response and group contrasts, but does not provide a minimum clinically important difference or detailed component-level changes. The ACR 20 definition combines joint counts with other assessments; the posted percentage does not reveal which components drove the response or how much participants improved beyond the required threshold.

The secondary outcomes offer additional context, but their interpretation is limited by the unreported multiplicity strategy and missing-data procedures. The listed HAQ-DI secondary outcome has no posted result in the registry record. Safety counts are segmented by treatment period and group, and should not be read as a simple randomized comparison across the full follow-up.

These findings are statistical descriptions of trial-group results. They are not individualized predictions, do not resolve all questions about benefits and harms, and do not imply a treatment choice for any person.

18. Why This Trial Matters Statistically

This trial illustrates why a statistical reading should consider more than whether a p-value crosses a conventional threshold. The group percentages describe the observed frequency of a defined response, percentage differences describe the contrast with placebo, confidence intervals indicate uncertainty in that contrast, and the outcome definition determines what counts as a response. Each piece answers a different question.

The comparison also demonstrates the distinction between the sponsor’s reported analysis and a simple recalculation from summary statistics. The registry names a Cochran-Mantel-Haenszel analysis, while a straightforward calculation from group summaries is unadjusted. They are not interchangeable analyses, even when they tell a similar story. Understanding that distinction prevents false precision and helps keep the reported inferential result in its proper context.

The registry’s treatment transitions are also important for interpretation. The primary endpoint is assessed during the placebo-controlled period, whereas later safety and secondary assessments may occur after treatment changes. Results from those different periods do not necessarily answer the same comparison question.

Finally, the record demonstrates how missing statistical-plan details constrain interpretation. The primary population is identified, and sponsor results are reported, but the registry does not specify missing-data procedures, a multiplicity strategy, or the original sample-size assumptions. Such omissions do not erase the posted findings; they define what can and cannot be concluded from the available record. Careful statistical interpretation preserves the observed signal while avoiding claims that require information not documented.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several limitations specific to this record affect interpretation. The registry reports the primary comparison method but not the Cochran-Mantel-Haenszel strata or other details needed to reproduce the sponsor’s analysis. The sponsor’s reported estimates can be interpreted as recorded, but the adjustment structure cannot be independently evaluated from this information.

The record does not report the missing-data method, the extent of missing primary or secondary endpoint values, or sensitivity analyses. Although the primary efficacy population includes all randomized participants by definition, that fact does not show how unavailable measurements were handled. No multiplicity approach is reported for the secondary endpoints or the full set of comparisons.

The endpoint is a binary composite threshold. It does not show continuous changes in the underlying assessments or identify which components contributed to response. A Week 24 change-from-baseline HAQ-DI outcome is listed, but its result is not reported in the registry record. A direct statistical comparison between the two sirukumab regimens is also not reported.

Safety entries are reported across treatment periods with differing group denominators and treatment histories. The placebo group transitions to sirukumab in later periods, limiting straightforward comparisons across those entries. Death counts are not reported in the registry record. The listed serious-event terms and counts do not alone establish whether an event was caused by treatment.

The registry does not report the original sample-size assumptions, eligibility details beyond the broad disease and prior-treatment description, or sufficient information to assess the impact of protocol deviations. These limits narrow the conclusions that can be drawn from the posted statistical record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study of CNTO 136 (Sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy (SIRROUND-T) — NCT01606761.
• Registry record last updated 2018-03-23; status last verified 2018-02.
• Results first posted 2018-02-05.
• 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.

23. Record Summary

NCT01606761 is a completed Phase 3 randomized, double-blind, placebo-controlled, parallel-group study of subcutaneous sirukumab in participants with active rheumatoid arthritis despite anti-TNF-alpha therapy. The primary endpoint was ACR 20 response at Week 16. The registry reports higher response percentages in both sirukumab groups than in the placebo group, with sponsor-reported percentage differences of 15.9 and 21.0 and p < 0.001 for each comparison.

The Week 24 secondary results show a broadly similar pattern for the posted binary outcomes, while the HAQ-DI result is not reported in the registry record. The sponsor analysis and unadjusted recalculations are broadly consistent in direction, and no discrepancy is flagged. Important analysis details, including missing-data handling and multiplicity procedures, are not reported in the registry record. Safety results are presented across treatment periods and should be interpreted in light of the changing treatment groups and denominators.