BI 695500 vs Rituxan First Line Treatment in Patients With Low Tumor Burden Follicular Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BI 695500 vs Rituxan First Line Treatment in Patients With Low Tumor Burden Follicular Lymphoma (NCT02417129), a randomized phase 3 study. The primary outcome is Overall Response Measured as Overall Response Rate (ORR) at Week 30 for BI 695500 Versus Rituximab.

2. Clinical Question

3. Trial Design

This was a Phase III, randomized, double-blind, parallel-arm, active-comparator trial sponsored by Boehringer Ingelheim. The intended comparison was BI 695500 against rituximab as first-line immunotherapy for patients with untreated low tumor burden follicular lymphoma. The planned allocation ratio was 1:1, and both treatment arms had the same stated dose and schedule: 375 mg/m2 by intravenous infusion once a week for 4 weeks, on Days 1, 8, 15, and 22.

The registry lists a start date of 2015-04 and a primary completion date of 2015-12. The trial status is terminated. The brief summary says disease assessments were to take place at the End of Study visit at Week 30. The primary endpoint description places the Week 30 response assessment approximately 26 weeks after completion of study treatment.

The intended balance between arms was not achieved in the treated participants: two participants were randomized and treated with BI 695500, while no patient was treated with rituximab. The registry record states that the program was prematurely discontinued and that only two patients had been randomized at that time. It does not report the reason for termination, the method used to generate or conceal the allocation sequence, or the operational details of maintaining blinding. Those details are not reported in the registry record.

The listed secondary outcomes were the extrapolated area under the concentration-time curve for BI 695500 or rituximab at steady state over the interval from zero hours to the next dose, and immunogenicity at Week 30. Results for these secondary outcomes 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: All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that the subject met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

Overall Study

Analysis population for the primary outcome, as defined in the registry: As the program was prematurely discontinued and only two patients were randomized at the time of discontinuation, the planned statistical analysis was not performed.

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: The randomized set (RS) includes all subjects who were randomized to a treatment. No patient was randomized to rituximab.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Measured as Overall Response Rate (ORR) at Week 30 for BI 695500 Versus Rituximab, measured over From first administration of study medication until 30 weeks thereafter..

The primary endpoint was overall response rate at Week 30. The endpoint counts participants with a complete response or partial response, as defined by International Working Group criteria 2007. An independent radiology assessment was specified. The timeframe is described as running from the first administration of study medication until 30 weeks thereafter, with the response assessment taking place approximately 26 weeks after treatment completion.

In general, an overall response endpoint combines complete and partial responses into a measure of how many participants meet either response category. It is used to summarize tumor response under defined criteria at a specified assessment time. A clear assessment time and common response criteria help make the endpoint interpretable across the treatment groups.

The trial’s stated objective was statistical equivalence between BI 695500 and rituximab for this endpoint. However, the registry record says the planned statistical analysis was not performed. It reports that two participants were treated with BI 695500 and none with rituximab, but it does not provide response counts by category or a calculated response rate. Therefore, an efficacy comparison cannot be read from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial was randomized, double-blind, and parallel-arm. Randomization is intended to assign participants by chance, reducing systematic differences between groups at baseline. Double-blinding is generally used to limit the influence of knowledge about treatment assignment on participant experience, clinical management, and outcome assessment. A parallel-arm design assigns participants to one treatment group for comparison with another. These are general purposes of the design features; the registry record does not report allocation-sequence methods, concealment procedures, or the practical details of blinding.

The planned allocation ratio was 1:1. The treated participants were not evenly represented across the two interventions: two received BI 695500 and none received rituximab. The planned ratio describes the intended design, not the observed allocation among treated participants. This imbalance leaves no treated comparator group for estimating the planned treatment contrast.

The primary outcome was a binary response classification at Week 30: complete response or partial response counted as overall response under the stated criteria. In general, a binary endpoint can be analyzed by comparing the proportion of participants with the event between groups. A valid comparison needs outcome information and denominators for both groups. The registry record does not provide response counts or an analysis for either group, and it says the planned statistical analysis was not performed. No statistical test or model for the primary endpoint is reported.

The objective was statistical equivalence. In general, an equivalence analysis assesses whether the treatment difference is sufficiently close to zero according to a prespecified margin. A confidence interval is often central to that assessment: the interval must be narrow enough to rule out differences beyond the acceptable margins. The registry record does not report an equivalence margin, the planned confidence-interval procedure, a testing strategy, or a completed estimate. These methodological details are not reported in the registry record, so the intended equivalence criteria cannot be reconstructed from the posted results.

A p-value, when reported, measures how incompatible the observed data are with a specified statistical null model, conditional on the model assumptions. It does not directly give the probability that treatments are equivalent, nor does a nonsignificant result alone demonstrate equivalence. No p-value is reported for this trial’s primary endpoint. With no treated participants in the rituximab group and no completed primary analysis, the record does not permit an inferential comparison.

The record identifies a planning illustration using a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Such calculations are planning illustrations, not the trial’s own design and not observed power. They do not replace the unperformed primary analysis or establish what the trial would have concluded. The registry record does not report the original sample-size justification or indicate that these illustrative assumptions were the basis for the trial’s design.

The primary endpoint was assessed by independent radiology review using International Working Group criteria 2007. Independent assessment can reduce the risk that knowledge of treatment assignment influences response classification. The record does not give further detail about review procedures or how disagreements, if any, were handled. It also does not report whether there were interim analyses, how missing response assessments would be treated, or which analysis population was planned for the primary comparison.

The endpoint is a participant count and response classification, rather than a time-to-event outcome. General issues such as over-dispersion are relevant to some count models when variability exceeds the model’s assumptions; they are not a reported method or an identified issue in this trial’s registry record. No fitted model, variance estimate, adjustment method, or sensitivity analysis is reported. In the absence of those analyses, the statistical record is descriptive of the trial’s small treated cohort and does not support a comparative efficacy estimate.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome of overall response rate at Week 30 and secondary outcomes relating to the steady-state extrapolated area under the concentration-time curve and immunogenicity at Week 30. It does not report a multiplicity strategy, such as an order for testing endpoints or an adjustment for making multiple comparisons. The planned statistical analysis was not performed, so there are no posted inferential results for which the impact of multiplicity can be assessed.

Missing-data procedures are not reported in the registry record. The record does not say how an absent Week 30 radiology assessment, an unevaluable response, or incomplete follow-up would have been handled. It also does not provide participant-level outcome status or a breakdown of assessment completion. The two participants treated with BI 695500 and the absence of rituximab-treated participants are reported, but that information does not establish whether all planned assessments were completed.

The registry record does not identify the analysis populations intended for efficacy or safety, such as whether analysis would follow randomized assignment, treatment received, or another defined set. It states that two patients were randomized and treated with BI 695500 and that no patient was treated with rituximab. The planned statistical analysis was not performed. Consequently, there is no reported analysis population, missing-data method, or sensitivity analysis to evaluate. These omissions matter because endpoint interpretation can depend on which participants are included and how incomplete measurements are handled; they cannot be resolved by assuming a conventional approach.

11. 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 non-serious adverse event terms

The safety figures list two participants at risk for BI 695500, with zero affected by serious adverse events and two affected by other adverse events. These are counts, not comparative rates that can establish a difference between treatments. The registry record lists zero participants at risk in the rituximab group because no patient was treated with rituximab. A group with no exposed participants cannot provide a safety comparison.

The registry record lists no serious adverse event terms. The deaths field is not populated with a count, so deaths are not reported in the registry record; it should not be read as a reported count of zero. The other adverse-event count is a separate category from serious adverse events, and the record does not give the event types or participant-level details in the registry record.

In general, safety counts describe events observed during the recorded exposure and follow-up; small exposure groups provide limited information about how frequently uncommon events might occur. Here, the BI 695500 group includes only two treated participants, and there is no treated comparator group. The figures therefore describe what was recorded for this very small cohort, not a reliable estimate of relative safety.

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

The record establishes that a Phase III randomized, double-blind comparison of BI 695500 and rituximab was planned for untreated low tumor burden follicular lymphoma, with overall response rate at Week 30 as the primary endpoint. It also establishes that the program was prematurely discontinued, with only two participants randomized and treated with BI 695500 and no participant treated with rituximab. The planned statistical analysis was not performed.

Those details do not establish whether the treatments had similar, different, or equivalent efficacy. No primary response counts, comparative estimate, confidence interval, or p-value are reported. The missing comparator exposure prevents the intended between-group comparison, and the absent response results prevent even a description of the BI 695500 response outcome. Equivalence cannot be inferred from the absence of a completed analysis.

Nor does the record show that the study found no effect or that a treatment failed. There is no reported result that supports either conclusion. The correct interpretation is that the registry record does not resolve the efficacy question. The same restraint applies to safety: the listed events describe two BI 695500-treated participants, with no rituximab-treated participants available for comparison.

In general, a trial’s ability to answer a question depends on adequate outcome information in the comparison groups and on an analysis suited to the question. A planned design does not itself provide evidence for an endpoint when the analysis was not performed. The registry record is therefore informative about the trial’s intended design, its premature discontinuation, and the limited exposure recorded, but not about comparative treatment effects.

13. Why This Trial Matters Statistically

This trial is statistically notable because its intended question was an equivalence question, but the observed treatment exposure did not permit the planned comparison. The design called for a randomized 1:1 allocation, yet the registry record reports two participants treated with BI 695500 and none treated with rituximab. This illustrates the distinction between a planned allocation and the data actually available for analysis.

Equivalence requires evidence that the treatment contrast lies within a prespecified range of acceptable differences. Merely having a small or incomplete trial, or lacking a statistically significant difference, cannot establish equivalence. In this record, the planned statistical analysis was not performed and the equivalence margin is not reported. The objective can be described, but it cannot be treated as an achieved conclusion.

The case also highlights the role of endpoint information. Overall response rate depends on classifying participants according to defined response criteria and comparing the resulting outcomes across groups. The registry gives the Week 30 endpoint definition and assessment approach, but does not give response counts or comparative estimates. The planned endpoint therefore remains unanswered in the posted results.

Finally, the safety record shows why exposure denominators matter. Counts from a small treated group are descriptive, and no comparator exposure means no direct safety contrast. The study is useful as an example of how clear design intentions and endpoint definitions are distinct from evidence generated by a completed analysis. The main statistical lesson is not a treatment conclusion, but the importance of interpreting results in light of who was treated, what outcomes were recorded, and whether the planned comparison was actually analyzed.

14. Limitations

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

The main trial-specific limitation is the very small treated cohort: two participants received BI 695500 and none received rituximab. The planned comparative analysis therefore could not be performed, as the registry record states. With no treated comparator group and no reported response outcomes, the primary efficacy question cannot be answered from this record.

The trial was terminated after premature discontinuation of the program. The reason for termination is not reported in the registry record. The record also does not report whether the two participants completed the Week 30 assessment, their response categories, or the handling of any missing outcome information. These omissions prevent evaluation of endpoint completeness and the planned analysis population.

Important methodological details are not reported in the registry record, including the equivalence margin, the detailed statistical analysis plan, the approach to multiplicity, and missing-data procedures. The record does not specify interim analyses or provide a sample-size justification for the trial’s original design. Without these details and without a completed analysis, the intended inferential framework cannot be fully evaluated.

The safety information is also limited by the small exposed group and the lack of rituximab exposure. The listed counts do not provide a useful comparative safety estimate, and deaths are not reported in the registry record. Secondary outcomes are identified, but their results are not reported. These limitations concern the information available in the registry record and should not be filled in by assumptions about the protocol or unposted results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: BI 695500 vs Rituxan First Line Treatment in Patients With Low Tumor Burden Follicular Lymphoma — NCT02417129.
• Registry record last updated 2017-01-30; status last verified 2016-12.
• Results first posted 2017-01-30.
• 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.

18. Record Summary

The registry record describes NCT02417129, a Phase III randomized, double-blind, parallel-arm trial sponsored by Boehringer Ingelheim. It planned to compare BI 695500 with rituximab as first-line immunotherapy for untreated low tumor burden follicular lymphoma. Both treatments were specified at 375 mg/m2 by intravenous infusion once a week for 4 weeks.

The primary outcome was overall response rate at Week 30, based on complete or partial response under International Working Group criteria 2007 and independent radiology assessment. The trial was terminated. The record states that the program was prematurely discontinued and that two participants were randomized and treated with BI 695500, while no patient was treated with rituximab. The planned statistical analysis was not performed. The registry record therefore does not report a comparative efficacy result or establish equivalence.