Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis (NCT01955733), a na phase 3 study. The primary outcome is The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase.

2. Clinical Question

3. Trial Design

NCT01955733 was a Phase 3, open-label extension trial of BI 695500 in adults with moderately to severely active rheumatoid arthritis. Its stated purpose was to evaluate long-term safety among people who had successfully completed treatment in Trial 1301.1. The registry lists an enrollment of 91 and identifies BI 695500 as the intervention. The treatment description specifies two intravenous infusions separated by 2 weeks.

The design is recorded as single-group, with allocation marked not applicable and no masking. Those features matter when interpreting the adverse-event figures: the extension was not a randomized comparison of BI 695500 against the treatments named in the adverse-event listing. The listed Rituxan and MabThera groups are identified as prior treatments from Trial 1301.1. They should not be read as concurrent control arms for this extension.

The registry lists a start date of 2013-05-31 and a primary completion date of 2015-11-18. The trial status is terminated. A reason for termination is not reported in the registry record, so the status alone does not establish why the trial ended or whether the intended follow-up was completed.

The primary outcome concerns the percentage of patients with drug-related adverse events during the treatment phase, with a Week 48 timeframe. Four secondary outcomes concern disease activity or response at Week 48: change in DAS28 using ESR, ACR20, ACR/EULAR remission, and EULAR response. Those secondary measures refer to improvement since baseline in Trial 1301.1. The registry lists five outcome measures overall, but no analysis entries. A statistical analysis plan, detailed allocation procedures for the parent trial, and the reason for stopping 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.

Before assignment: 97 subjects were screened for eligibility to participate in this extension trial. 91 subjects met all inclusion and exclusion criteria and were assigned to receive treatment.

Period 1

Reasons for not completing this period:

Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Randomized Analysis Set (SAFRD): All subjects randomized in 1301.1 \[excluding open-label safety run-in subjects of trial 1301.1\] who receive at least one dose of trial medication and subjects will be classified according to treatment received in trial 1301.1. 2 subjects from 1301.1 safety run-in also received treatment in 1301.4, thus 88.

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: Safety Randomized Analysis Set \[SAFRD\]: All subjects randomized in 1301.1 \[excluding open-label safety run-in subjects of trial 1301.1\] who receive at least one dose of trial medication and subjects will be classified according to treatment received in trial 1301.1. 2 subjects from 1301.1 safety run-in also received treatment in 1301.4, thus 88.

6. Primary Endpoint

The registry lists the primary outcome as The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase, measured over Week 48.

The primary endpoint is the percentage of patients with drug-related adverse events during the treatment phase, assessed at Week 48. It is a binary-event summary: each participant contributes to whether an event meeting the endpoint definition occurred, and the result is expressed as a percentage of patients. The endpoint description identifies treatment-emergent adverse events as events that began or worsened in severity on or after the first dose of trial medication in the extension, through the last date of trial medication plus 180 days, inclusive. An event was considered drug-related when the investigator judged that it had a causal relationship to trial medication.

Safety endpoints of this kind are used to describe the frequency of events during treatment and the period specified for capturing them. They can help characterize what was observed in the treated population, but an event percentage alone does not establish that the drug caused an event. The endpoint’s drug-related classification is based on investigator judgment, while the treatment-emergent definition describes timing relative to dosing.

The record does not give the primary endpoint’s numerical percentage, event count, or confidence interval. As a result, the endpoint definition can be described, but its estimated frequency and precision cannot be assessed from the registry record. The adverse-event figures reported elsewhere in the record are not identified as the numerical result for this primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a percentage endpoint and provides some event counts, but it does not report an analysis method for the primary outcome. No analysis entries are listed. The explanation below distinguishes what can be read directly from the record from general statistical concepts that help interpret this kind of outcome.

What does a percentage endpoint represent?

General concept: For a binary outcome, each participant is classified according to whether the defined event occurred during the specified observation period. A percentage summarizes the fraction of participants meeting that definition. It is important that the event definition, observation window, and analysis population are clear because each determines who and what is counted.

In this trial, the endpoint is the percentage of patients with drug-related adverse events during the treatment phase, with Week 48 given as the timeframe. The description defines treatment-emergent events by when they began or worsened relative to the first dose and the end of trial medication, with an additional 180-day period included. Investigator judgment determines whether an event is considered related to the medication. These criteria describe the endpoint, but the numerical endpoint estimate itself is not reported in the registry record.

Why does the analysis population matter?

General concept: An analysis population specifies which participants contribute to an estimate. A safety population commonly focuses on those who received treatment, because exposure is needed for describing events during treatment. Different population definitions can yield different results when participants are excluded or classified differently. The population definition should therefore be read alongside any outcome estimate.

The primary outcome description names a Safety Randomized Analysis Set. It refers to participants randomized in Trial 1301.1, excluding open-label safety run-in subjects, who received at least one dose of trial medication, and says classification follows treatment received in Trial 1301.1. The text is incomplete after mentioning additional subjects, so the full population definition is not reported in the registry record. The enrollment of 91 describes the trial overall; it does not by itself establish the denominator used for each outcome.

What can counts and percentages tell readers?

General concept: Counts show how many events or participants were observed, while denominators show the population in which those counts arose. A percentage expresses the count relative to its denominator. Neither a count nor a percentage alone gives the full picture of uncertainty, event severity, duration, or causality. A confidence interval, when reported, communicates the statistical uncertainty associated with an estimate under the chosen method.

The serious and other adverse-event listings include counts and numbers at risk for three groups. Those group labels distinguish BI 695500 from Rituxan From 1301.1 and MabThera From 1301.1. The record says this is not a randomized comparison and the groups are not like-for-like controls. Thus, the counts are descriptive and should not be converted into causal conclusions or treated as estimates of comparative treatment effects. No confidence intervals for these figures are reported in the registry record.

Why is a nonrandomized comparison limited?

General concept: Randomization is used to make treatment groups comparable, on average, with respect to measured and unmeasured characteristics. When groups are not assigned concurrently by randomization, observed differences may reflect differences in participants, prior treatment, exposure, or follow-up rather than a treatment effect. Statistical adjustment can sometimes address measured differences, but it cannot automatically remove unmeasured differences.

This extension is recorded as single-group, with allocation not applicable and no masking. The adverse-event categories that refer to prior treatments in Trial 1301.1 do not constitute randomized comparator arms in this extension. The record reports no adjusted comparative estimates or inferential analysis for these group figures. Any direct comparison would therefore go beyond what the design and posted results support.

What do the registry entries not establish?

General concept: A statistical analysis plan documents choices such as how outcomes are summarized, how uncertainty is estimated, how missing observations are handled, and whether any formal comparisons are planned. Without those details, readers cannot determine whether a particular analysis was prespecified or how it treated incomplete follow-up.

The registry record lists five outcome measures and zero analyses. It does not report the primary endpoint result, a confidence interval, a missing-data method, a multiplicity procedure, or a sample-size justification. These absences do not prove that no analyses or procedures were conducted; they mean that they are not reported in the registry record. The sample-size assumptions associated with planning illustrations describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. No resulting sample-size figures or observed effect are included in the record, and such planning illustrations would not be observed power.

General statistical interpretation also distinguishes between a lack of a reported estimate and evidence that an event did not occur. Because the primary endpoint’s numerical result is absent, no conclusion about its magnitude or precision can be drawn from the endpoint description alone. The adverse-event counts provide a limited descriptive view, not a substitute for the primary endpoint estimate or a formal comparison.

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("BI 695500", "Rituxan From 1301.1", "MabThera From 1301.1")
n      <- c(30, 29, 29)
events <- c(5, 2, 1)
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  BI 695500  30  5  16.7  5.6  34.7  7.3  33.6  7.5  33.7
ARM  Rituxan From 1301.1  29  2  6.9  0.8  22.8  1.9  22.0  2.1  22.1
ARM  MabThera From 1301.1  29  1  3.4  0.1  17.8  0.6  17.2  0.8  17.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures: the primary drug-related adverse-event endpoint and four secondary measures of disease activity or response at Week 48. The secondary measures include change in DAS28 using ESR, ACR20, ACR/EULAR remission, and EULAR response, each described relative to baseline in Trial 1301.1. The record lists zero analyses, so it does not report which outcomes were formally tested, in what order, or whether any adjustment was planned for multiple outcomes.

General concept: When several outcomes are tested, the chance of at least one apparently notable result can increase if each is interpreted without regard to the number of tests. A multiplicity plan can specify which outcomes are confirmatory and how statistical error is controlled. No such plan is reported in the registry record, so the intended inferential status of the secondary outcomes cannot be established.

Missing-data methods are also not reported in the registry record. The outcome description gives a safety analysis population, but does not specify how participants with incomplete follow-up, missing event information, or treatment discontinuation were handled. These details matter because the observation period extends beyond the last date of trial medication, and follow-up completeness can affect a percentage estimate.

A sample-size justification and the protocol’s statistical plan are not reported in the registry record. Planning assumptions for an illustration are not the same as the trial’s own design rationale, and sample-size illustrations are not observed power. Since no primary-endpoint estimate or analysis details are listed, precision and the impact of missing observations cannot be evaluated.

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: cellulitis (6.9%), femur fracture (3.4%), hypoglycaemia (3.4%), metabolic acidosis (3.4%), cerebral microangiopathy (3.4%).

The serious adverse-event figures are listed as counts among participants at risk: BI 695500 has 0 serious events among 30 at risk; Rituxan From 1301.1 has 2 among 29; and MabThera From 1301.1 has 2 among 29. The other adverse-event counts are 7 among 30, 8 among 29, and 9 among 29, respectively. These are descriptive registry figures, not results from randomized comparison arms in the extension.

The record identifies the listed treatment labels as referring to prior treatment in Trial 1301.1 and cautions that the groups are not like-for-like controls. The figures therefore do not establish that one treatment caused more or fewer events than another. The registry record does not provide confidence intervals, a comparative analysis, or a full account of event duration and clinical context for these counts.

Among the listed serious-event terms, cellulitis is reported at 6.9%; femur fracture, hypoglycaemia, metabolic acidosis, cerebral microangiopathy, and metabolic encephalopathy are each reported at 3.4%. These percentages describe the terms as listed, but the record excerpt does not give the corresponding term counts or a group-specific breakdown. The primary endpoint’s drug-related adverse-event percentage is not reported, and these serious-event figures should not be mistaken for that endpoint result.

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

The registry record establishes that this was an open-label extension intended to assess long-term safety of BI 695500 in adults with moderately to severely active rheumatoid arthritis who had completed treatment in Trial 1301.1. It also specifies the primary safety endpoint, the event definition, the Week 48 timeframe, and selected adverse-event counts. Those details allow readers to understand what the trial set out to measure and to describe some reported safety observations.

The record does not give the numerical result for the primary endpoint: the percentage of patients with drug-related adverse events during the treatment phase. It also does not provide an uncertainty interval or a formal analysis for that outcome. The reported serious and other adverse-event counts are limited descriptive information, and the historical treatment labels do not create a randomized control comparison. They cannot establish a causal difference between treatments.

The listed secondary outcomes address disease activity and response, but numerical results for them are not included in the registry record reported in the registry record. Therefore, no conclusion about the magnitude or precision of those outcomes can be drawn from this record.

General interpretation: A study’s objective, design, and observed event counts answer different questions. An objective tells readers what investigators intended to assess; a design describes how participants were treated and compared; and an estimate with uncertainty describes what the data support quantitatively. Here, the design and endpoint definition are available, but the primary estimate and its precision are not. The record therefore supports a careful account of the trial structure and selected counts, not a conclusion that BI 695500 did or did not cause a particular level of risk or change in disease activity.

The trial status is terminated, but the reason for termination is not reported in the registry record. That status by itself does not explain whether the study stopped for safety, operational, recruitment, or other reasons. No such explanation should be inferred from the status alone.

14. Why This Trial Matters Statistically

This trial illustrates why safety studies require both a clear event definition and a clearly reported denominator. The primary endpoint is not simply any adverse event: it is restricted to treatment-emergent events within a specified period and then further classified as drug-related by investigator judgment. These choices shape what the percentage represents. Without the numerical endpoint result and analysis population details, readers can understand the intended measure but cannot assess its observed frequency.

It also shows the distinction between an extension’s treatment structure and labels carried forward from an earlier trial. The record describes a single-group, open-label extension, while the adverse-event figures are split by treatment received in Trial 1301.1. Those labels may be useful for describing the listed data, but they do not turn the extension into a randomized comparison. Statistical interpretation must follow the design, not the appearance of multiple group labels.

The record further demonstrates why counts should be accompanied by context and uncertainty. The serious-event counts are small descriptive summaries for the groups listed, and no confidence intervals or comparative analyses are reported. The most frequent serious-event terms have percentages, but no term counts or group-level breakdowns are given in the registry excerpt. Readers cannot infer precision from a percentage alone.

Finally, the registry lists outcome measures but no analyses. This leaves open important questions about missing data, multiplicity, and the intended inferential role of secondary outcomes. These omissions do not show that analyses were never conducted; they limit what can be verified from the registry record. For clinical researchers, the example underscores the value of reporting estimates, uncertainty, analysis populations, and prespecified methods alongside endpoint definitions.

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 record does not report a numerical result for the primary endpoint. There is no endpoint percentage, count, or confidence interval available to assess the frequency or precision of drug-related adverse events during the treatment phase. The endpoint definition is described, but that is not a substitute for an estimate.

The trial is an open-label, single-group extension with allocation marked not applicable. The adverse-event figures are divided by treatment labels from Trial 1301.1, and the record explicitly warns that they are not a randomized, like-for-like comparison. Differences between those figures cannot be interpreted as causal treatment effects. No comparative or adjusted analyses are reported.

The record reports an enrollment of 91, while the adverse-event listings give at-risk denominators for their labeled groups. These are different pieces of information, and the overall enrollment should not be assumed to be the denominator for every outcome. The full analysis-population description is incomplete in the record, which also limits interpretation of who contributed to each safety summary.

Methods for handling missing event information or incomplete follow-up are not reported in the registry record. Nor are confidence intervals, multiplicity procedures, the trial’s sample-size justification, or a complete statistical analysis plan. The secondary outcomes are named, but numerical results are not reported in the material summarized by the registry fields. The reason for the terminated status is also not reported, so no explanation for termination can be inferred from that designation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis — NCT01955733.
• Registry record last updated 2018-01-18; status last verified 2017-12.
• Results first posted 2018-01-18.
• 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

NCT01955733 is a Phase 3, open-label extension trial of BI 695500 in adults with moderately to severely active rheumatoid arthritis who successfully completed treatment in Trial 1301.1. The registry lists 91 enrolled participants and describes two intravenous infusions separated by 2 weeks. The trial is recorded as single-group, with allocation not applicable and no masking; its status is terminated.

The primary outcome is the percentage of patients with drug-related adverse events during the treatment phase at Week 48. The registry defines treatment-emergent events by timing relative to dosing and identifies drug-related events through investigator judgment. It does not report the numerical primary-endpoint result. Serious and other adverse-event counts are listed by prior treatment labels, but the record cautions that these are not like-for-like randomized comparison groups. The reason for termination, analysis plan, missing-data methods, and multiplicity approach are not reported in the registry record.