Efficacy and Safety Study of R935788 Tablets to Treat Rheumatoid Arthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of R935788 Tablets to Treat Rheumatoid Arthritis (NCT00665925), a randomized phase 2 study. The primary outcome is American College of Rheumatology 20 (ACR20) Response at 6 Months.

2. Clinical Question

3. Trial Design

This was a Phase II, randomized, double-blind, placebo-controlled, parallel-dose study sponsored by Rigel Pharmaceuticals. The registry lists quadruple masking. The design compared two oral R788 regimens with placebo in people with rheumatoid arthritis who had not responded adequately to methotrexate. One active regimen was 100 mg twice a day, and the other was 150 mg once a day. Placebo was administered once or twice a day.

The registry records enrollment of 457 and gives the study status as completed. The recorded study start was 2008-05, with primary completion in 2009-06. The primary outcome was ACR20 response at six months. The record also lists ACR20 response at earlier follow-up points, alongside other secondary measures.

The primary outcome record describes an intent-to-treat population that includes all subjects who received study drug. The posted primary counts are 53 participants in the pooled placebo group, 87 in the 150 mg once-daily group, and 101 in the 100 mg twice-daily group. Their associated group sizes are 153, 152, and 151, respectively. These are descriptive counts, not a reported adjusted treatment comparison.

Although randomization and masking are recorded, the registry record does not report the sequence-generation method, concealment procedures, or who was included in the term quadruple masking. Details of dose allocation, treatment adherence, withdrawals, and the handling of protocol deviations are not reported in the registry record. A rationale for the enrollment target and a full statistical analysis plan are also not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Male/female participants who had active rheumatoid arthritis (RA) for a minimum of 6 months, and receiving a weekly methotrexate (MTX) dose for a minimum of 3 months were randomly assigned to receive R788 150 mg once daily, 100 mg twice daily, placebo once daily or placebo twice daily. It was planned to randomize approximately 420 participants.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat population includes all subjects that received study drug

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 American College of Rheumatology 20 (ACR20) Response at 6 Months, measured over 6 months.

The primary endpoint is the number of participants with an ACR20 response at six months. The registry defines response as at least 20% improvement in both tender and swollen joint counts, together with improvement in any three of these measures: physician assessment of disease activity, patient assessment of disease activity, patient assessment of pain, HAQ-DI, and C-reactive protein or erythrocyte sedimentation rate.

This is a binary outcome: each participant either meets the stated response definition or does not. Reporting the number who meet the definition makes the endpoint easy to interpret as a count, but counts alone do not describe the uncertainty around a treatment contrast. The posted primary results do not include a confidence interval or a hypothesis test for a comparison between either active regimen and placebo.

In general, a composite response measure can capture more than one aspect of a condition by requiring improvement across specified components. Here, improvement in joint counts is necessary, and improvement in additional assessments and an inflammatory marker is also required. ACR20 therefore describes whether the participant crossed the registry’s defined response threshold; it does not report the size of improvement for each component, nor does it show how the components changed individually.

The registry record identifies the primary population as intent-to-treat and specifies that it includes all subjects who received study drug. It does not describe how missing component measurements or missing follow-up data were treated when determining response.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Outcome type and event counts. The primary endpoint is binary because each participant is classified as meeting or not meeting the ACR20 response criteria at six months. The registry posts the number meeting the definition and the number in each group. In general, a binary outcome can be summarized with an event count and denominator, and groups can be compared using a risk difference or a relative measure such as a risk ratio. The primary outcome record does not include a reported comparative estimate.

How to read a confidence interval

In general, a confidence interval describes statistical uncertainty around an estimate. A narrower interval indicates greater precision under the method’s assumptions; a wider interval indicates less precision. For a risk difference, zero represents no difference between the compared groups. An interval that includes zero is compatible with no difference under that interval procedure, as well as with effects in either direction that remain within its bounds. This interpretation is not a statement about clinical importance.

The secondary ALT comparisons report risk differences and confidence intervals. Several have broad intervals, reflecting limited precision in comparisons with relatively few recorded events. The interval should be interpreted together with the estimate and the underlying event counts; it is not a guarantee that the true effect falls within the displayed bounds.

How to read an unadjusted p-value

In general, a p-value measures how incompatible the observed data are with a specified null hypothesis, assuming the model and other test assumptions hold. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of an effect. A p-value also does not account for the number of outcomes or comparisons unless a multiplicity procedure is explicitly applied.

The secondary ALT results include unadjusted p-values. They should be read as results for individual comparisons, not as multiplicity-adjusted evidence across all outcomes. The registry record does not report multiplicity adjustment or a prespecified hierarchy for the secondary outcomes. No p-value is reported for the primary ACR20 comparison.

Why denominators matter

Counts need their corresponding group sizes because an identical event count can represent different event frequencies in groups of different sizes. The posted primary endpoint gives a denominator for each listed group, allowing the counts to be understood in context. No additional response proportions or contrasts are calculated in this interpretation.

The primary population is described as intent-to-treat and includes all subjects who received study drug. That wording does not fully specify how the registry handled missing assessments, treatment discontinuation, or participants without an evaluable response. Those details are not reported in the registry record.

What the planning illustrations mean

Sample-size calculations based on observed effects are planning illustrations rather than observed trial results. In general, such calculations ask how many participants per arm would be needed under stated assumptions to detect a chosen effect with a chosen power. The registry’s stated assumptions for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. The calculations are not the trial’s original design justification and are not observed power.

Planning estimates based on an observed effect can be unstable, especially when the event counts are limited or the estimate is uncertain. Considering smaller fractions of the observed effect can illustrate how the required number of participants changes under the calculation assumptions. These values should not be read as proof that a future study will achieve a particular result. The registry record does not report the original sample-size justification.

Why over-dispersion is not the central issue

Over-dispersion is a general concern when a model assumes more uniformity in outcome variation than the data support, commonly in count or clustered data. The endpoint is a participant-level binary response, and the posted primary result is a count with a denominator. The registry record does not describe a model for the primary endpoint, so it is not possible to assess whether any particular variance or modeling assumption was used. For the reported secondary risk differences, uncertainty is conveyed through the stated intervals, but the analysis details are not reported in the registry record.

The registry lists zero reported analyses for the primary record and no reported analyses for the listed secondary comparisons. Thus, the posted outcome values and the simple unadjusted comparisons available for selected secondary outcomes should be distinguished from a fully documented analysis plan and sponsor-reported inferential analysis. The registry record does not report the estimation methods, covariate adjustments, or sensitivity analyses for the primary endpoint.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Arm 3 - Placebo Pooled", "Arm 4 - R788 150 mg qd", "Arm 5 - R788 100 mg Bid")
n      <- c(153, 152, 151)
events <- c(53, 87, 101)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Arm 3 - Placebo Pooled  153  53  34.6  27.1  42.7  27.6  42.5  27.6  42.5
ARM  Arm 4 - R788 150 mg qd  152  87  57.2  49.0  65.2  49.3  64.8  49.3  64.8
ARM  Arm 5 - R788 100 mg Bid  151  101  66.9  58.8  74.3  59.0  73.9  59.0  73.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists numerous secondary outcomes, including ACR20 response at several follow-up times and other clinical or laboratory measures. When many outcomes and comparisons are examined, the chance of obtaining one or more apparently notable results by chance can increase. In general, multiplicity procedures, a prespecified hierarchy, or clearly designated exploratory analyses can help readers understand how such results should be interpreted.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or which secondary analyses were designated as confirmatory versus exploratory. The ALT comparison p-values are unadjusted. They therefore describe individual comparisons without accounting for the broader set of posted outcomes. Their interpretation should remain cautious, particularly because the registry does not provide a complete account of the analysis plan.

Missing-data handling is also not reported in the registry record. The primary endpoint population is described as intent-to-treat and includes all subjects who received study drug, but the record does not explain what happened when a participant lacked a six-month assessment or had incomplete information for one of the ACR20 components. It does not state whether missing observations were imputed, counted as nonresponse, or handled by another method.

The available record also does not detail participant flow, discontinuations, adherence, or sensitivity analyses addressing missing outcomes. These omissions limit assessment of how closely the posted results reflect the randomized groups and how robust the results might be under alternative missing-data assumptions.

Consequently, the posted counts and secondary comparisons can be described, but the impact of missing data and multiple testing cannot be quantified from the registry record. The absence of these details is not evidence that a particular method was or was not used; the methods are simply not reported in the registry record.

12. 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: arthritis infective (1.3%), cellulitis (1.3%), soft tissue infection (1.3%), arthritis (1.3%), transient ischaemic attack (1.3%).

The safety record lists serious adverse events separately for placebo once daily, placebo twice a day, R788 150 mg once daily, and R788 100 mg twice a day. The corresponding serious-event counts are 2 among 77, 4 among 76, 5 among 152, and 1 among 152. These are group-level counts and denominators; they should be read as descriptive safety information rather than as a comparative causal analysis.

The registry also lists other adverse events for the same groups: 26 among 77, 20 among 76, 62 among 152, and 73 among 152. The record identifies several serious adverse event terms at 1.3% each. These term listings do not indicate that every event was related to study treatment. The record does not report a causal assessment in the information.

Serious-event counts do not show the timing, duration, recurrence, or clinical course of events. They also do not, by themselves, account for differences in follow-up or exposure. Deaths are not reported in the registry record. The safety figures should therefore be interpreted as posted counts, not as evidence that a regimen caused or prevented an event.

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

The primary outcome provides a direct count of participants who met a specified response threshold at six months in each listed group. It is useful as a descriptive result because it makes the endpoint and the observed event counts explicit. The record also makes clear that the response definition includes both joint-count improvement and improvement in additional assessments and an inflammatory marker.

Those counts do not, by themselves, tell how precisely the groups differ. The registry record does not report a primary risk difference, confidence interval, or p-value. Without a reported comparative analysis, the primary results cannot establish whether the observed differences in counts are compatible with chance variation, nor can they quantify the uncertainty around a treatment contrast.

The endpoint is a threshold outcome. It records whether the response definition was met, not the degree of improvement beyond that threshold, the pattern of change in each component, or the duration of response. It also does not, by itself, describe other aspects of participants’ experience or safety.

The secondary ALT results address a separate set of outcomes and are presented as unadjusted comparisons. They can inform a descriptive reading of the posted laboratory events, but the lack of a reported multiplicity strategy and the absence of a documented primary comparison limit how strongly those results can support an overall conclusion.

More broadly, registry results are a record of the information posted there. They do not necessarily provide all details needed to reproduce an analysis or assess all design and reporting decisions. Missing-data methods, the full statistical plan, and reported analyses are not reported in the registry record. This means the results can be described with precision about what is posted, while conclusions about comparative effects must remain limited by the unavailable methods and estimates.

14. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between reporting outcome counts and reporting a comparative treatment effect. The registry gives the number meeting the primary ACR20 response definition in each group and the corresponding group sizes. Those values are necessary for understanding the observed outcome, but they are not a substitute for an effect estimate with uncertainty.

For a randomized comparison, readers generally need to know the contrast being estimated, how uncertainty was calculated, and how the analysis handled departures from complete follow-up. In this record, the primary comparative estimate and its confidence interval are not reported. The result can therefore be described at the group level, but its statistical precision cannot be assessed from the posted primary results.

The record also highlights the importance of distinguishing a primary outcome from a broad set of secondary outcomes. Secondary measures can provide useful context, but unadjusted tests across many outcomes need cautious interpretation. Without a reported multiplicity plan, it is difficult to know whether an isolated secondary result was intended as confirmatory or exploratory.

Finally, planning illustrations based on observed effects should not be confused with the original enrollment rationale or with observed power. They describe hypothetical future study requirements under stated assumptions. The registry record does not report the original sample-size justification. Together, these features show why transparent reporting of the analysis plan, missing-data decisions, and primary treatment contrast is essential for interpreting trial results.

15. Limitations

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

The primary limitation for statistical interpretation is that the registry posts group-level ACR20 counts but no primary comparative estimate, confidence interval, or p-value. This prevents a direct assessment of the estimated contrast and its precision from the primary outcome record.

The record describes the primary population as intent-to-treat and says it includes all subjects who received study drug, but it does not report how missing six-month assessments or incomplete response components were handled. Participant flow, withdrawal details, adherence, and sensitivity analyses are not reported in the registry record. The effect of these unreported choices cannot be determined from the posted counts.

The registry reports secondary comparisons for ALT outcomes with unadjusted p-values, but does not report a multiplicity method or testing hierarchy. Because the record includes many secondary outcomes, individual secondary findings should not be treated as definitive in isolation. The registry also lists no reported analyses for these comparisons.

The safety record provides event counts by group, but does not provide event-level timing or a reported causal assessment in the information. Deaths are not reported in the registry record. These data are therefore limited for comparing safety beyond the posted descriptive counts.

Additional trial details—including the randomization procedure, allocation concealment, the specific roles covered by quadruple masking, and the original sample-size justification—are not reported in the registry record. These gaps constrain assessment of the design and analysis, but they do not establish that a particular method was absent or inadequately performed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of R935788 Tablets to Treat Rheumatoid Arthritis — NCT00665925.
• Registry record last updated 2016-09-16; status last verified 2016-08.
• Results first posted 2016-06-13.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00665925 is a completed Phase II randomized, double-blind, placebo-controlled, parallel-dose study sponsored by Rigel Pharmaceuticals. It enrolled 457 participants with rheumatoid arthritis and evaluated R788, 100 mg twice a day, and R788, 150 mg once a day, against placebo. The study record gives a start of 2008-05 and primary completion in 2009-06.

The primary outcome was ACR20 response at six months. The posted counts are 53 among 153 in pooled placebo, 87 among 152 with R788 150 mg once daily, and 101 among 151 with R788 100 mg twice a day. The registry record does not report a primary comparative estimate or its uncertainty. Secondary outcomes include ACR20 responses at other follow-up points and laboratory measures; selected ALT comparisons are posted as unadjusted analyses.

The record does not report the primary analysis methods, missing-data handling, multiplicity strategy, or original sample-size justification. Safety counts are listed by the separate placebo and active regimens, with deaths not reported in the registry record.