An Open-label, Multi-center Clinical Trial of Eculizumab in Adult Patients With Atypical Hemolytic-uremic Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open-label, Multi-center Clinical Trial of Eculizumab in Adult Patients With Atypical Hemolytic-uremic Syndrome (NCT01194973), a na phase 2 study. The primary outcome is Percentage of Patients With Complete TMA Response.

2. Clinical Question

3. Trial Design

This was a phase 2, open-label, multicenter clinical trial of eculizumab in adult patients with atypical hemolytic-uremic syndrome. The registry describes a single-group model, with allocation recorded as not applicable and masking recorded as none. Thus, the design does not include a randomized treatment assignment or a masked comparison. The trial is listed as completed, with enrollment recorded as 44. The start is recorded as 2010-07 and primary completion as 2013-10.

The registry’s stated purpose was to assess eculizumab for control of thrombotic microangiopathy (TMA) in adults with aHUS. The description links TMA to thrombocytopenia, hemolysis, and renal impairment. Eculizumab is the sole listed intervention, and the arm description contains no additional treatment details. The dose, route, schedule, treatment duration, and criteria for continuing or discontinuing treatment are not reported in the registry record.

A single-group design can describe outcomes observed among participants receiving the intervention, but it does not by itself estimate a treatment contrast against a concurrent control group. Because the trial was open-label, masking of participants and study personnel was not used. Whether outcome assessors were separately masked is not reported in the registry record. The record also does not report a protocol-level account of how the multicenter sites contributed participants or how site effects were handled in the analyses.

The record lists 12 outcome measures and 2 analyses. The primary outcome is the percentage of participants with complete TMA response through 26 weeks. Several secondary outcomes concern hematologic response, platelet count, estimated glomerular filtration rate, and TMA response. Their definitions and results are not all reported in the registry record. The primary outcome result itself, including the response estimate and its confidence interval, is not reported in the registry record, so the trial’s observed primary response cannot be described from the available information.

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: At screening, patients had to have signs or symptoms of hemolysis; serum creatinine level ≥ ULN and platelet count \< LLN

Screening Period

Reasons for not completing this period:

26 Week Treatment Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The tabulations of the proportions of patients with Complete TMA Response through 26 weeks were performed for the ITT population. Exact binomial two-sided 95% CI using the Clopper-Pearson method for the responder rate was presented.

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 intent-to-treat (ITT) population was defined as all patients who received any amount of eculizumab, and were considered evaluable for safety and efficacy analyses. For both the efficacy and safety analyses, all 41 patients who were treated with study drug were included in the ITT population.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Patients With Complete TMA Response, measured over Through 26 weeks.

The primary endpoint is the percentage of participants with complete TMA response through 26 weeks. The registry defines a response as normalization of hematological parameters—platelet count and LDH—together with preservation of renal function. Renal preservation is defined as less than a 25% increase in serum creatinine from baseline. The required findings had to be sustained for at least two consecutive measurements obtained at least four weeks apart.

This composite endpoint brings together blood and kidney measures relevant to the trial’s stated goal of controlling TMA. Requiring both hematological normalization and preserved renal function makes the endpoint more demanding than improvement in only one component. Requiring sustained findings across measurements also distinguishes a continuing response from a single measurement meeting the criteria. These are general reasons a trial may use a composite and persistence requirement; they do not establish how participants in this trial actually responded.

The registry specifies an exact binomial, two-sided 95% confidence interval using the Clopper-Pearson method for the responder rate, with tabulations for the ITT population. However, the response proportion and confidence interval are not reported in the registry record. The operational rules for handling missing measurements or participants who did not complete follow-up are also not reported. Therefore, the endpoint definition can be described, but its observed frequency and precision cannot be assessed from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary outcome as a responder proportion in the ITT population and specifies an exact binomial two-sided 95% confidence interval using the Clopper-Pearson method. This is a method for estimating a proportion and expressing uncertainty around it. The outcome counts a participant as a responder only if the defined criteria are met; the proportion is then based on responders relative to the analysis population. The registry record does not report the numerator, denominator, resulting proportion, or confidence limits, so none can be interpreted.

What does a confidence interval convey?

In general, a confidence interval gives a range of values compatible with the observed data under a stated statistical procedure. Its width reflects statistical precision: a narrower interval indicates greater precision under that procedure, while a wider interval indicates less precision. It is not a guarantee that the true value lies in the particular interval, and it does not account automatically for design limitations such as the absence of a control group. Since the primary confidence interval is not reported in the registry record, the precision of the primary response estimate cannot be evaluated.

Why use an exact binomial method?

For a binary outcome, each participant is classified according to whether the event or response occurred. The binomial model is a standard way to describe a proportion when observations are treated as binary outcomes. The Clopper-Pearson procedure constructs an exact interval rather than relying on a normal approximation to the distribution of the proportion. In general, exact methods can be useful when the number of observations or the number of responses is limited, or when the proportion is near a boundary. The record identifies this method but does not report the data needed to reproduce or check its result.

The phrase two-sided indicates that the interval allows for uncertainty in both directions around the estimate. The stated confidence level is 95%. A confidence interval is distinct from a hypothesis test: the registry information does not provide a primary-outcome p-value or a test comparing treatment groups. Because the design is single-group, the specified interval concerns a responder rate, not a randomized treatment effect.

What does the endpoint definition contribute?

The endpoint is composite: it requires normalization of platelet count and LDH, plus preservation of renal function as defined by the serum-creatinine criterion. It also requires the criteria to be sustained across consecutive measurements separated by at least four weeks. In general, a composite endpoint can capture more than one clinically relevant domain, but its overall result depends on all of its component requirements. The registry does not report component-specific primary results or the number of participants who met some, but not all, of the criteria. It is therefore not possible to determine which component most often limited complete response.

The persistence requirement is part of the endpoint definition, not a separate statistical adjustment. It means that an isolated qualifying measurement would not meet the stated definition. The registry does not report the timing or completeness of measurements for individual participants, so the effect of measurement availability on classification cannot be assessed.

How should the analysis population be understood?

The record says the primary-outcome tabulations were performed for the ITT population. In general, an intention-to-treat approach aims to analyze participants according to their assigned group, regardless of later treatment changes. This study is recorded as single-group, with allocation not applicable, and the registry information does not define how ITT membership was operationalized. It also does not report the number included in the primary analysis or how missing outcome data were handled. No specific rules for imputation, exclusion, or sensitivity analysis are reported in the registry record.

These details matter because a responder proportion depends on who is counted in its denominator and how participants with incomplete follow-up are classified. If missing measurements affect whether the sustained-response criteria can be assessed, the handling rule may influence the estimate. Without a reported denominator and missing-data approach, readers cannot fully reconstruct the analysis or assess the potential influence of incomplete observations.

What can the planning assumptions show?

The record describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. These are planning assumptions, not a description of the trial’s single-group design. Such illustrations are not observed power and do not establish that the trial was designed or sized according to those assumptions. The numerical planning results and the observed effect are not reported in the information available for this analysis. A justification for the trial’s enrollment target is not reported in the registry record.

More generally, sample-size calculations depend on assumptions about the effect, variability or event rate, allocation, and chosen error rate. They are prospective planning tools, not a measure of the probability that a finding is true after data have been collected. The stated illustrations should therefore be kept separate from interpretation of the trial’s observed outcomes, especially because the described illustrations assume a two-arm comparison while the registered trial is single-group.

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("Eculizumab")
n      <- c(41)
events <- c(30)
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  Eculizumab  41  30  73.2  57.1  85.8  58.1  84.3  58.0  84.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and 2 analyses, including the primary endpoint and secondary outcomes related to hematologic response, platelet count, estimated glomerular filtration rate, and TMA response. Multiple endpoints can create multiplicity: when many outcomes or analyses are examined, the chance of at least one apparently notable result may increase. In general, a prespecified hierarchy or adjustment can help address this issue, but the multiplicity strategy for this trial is not reported in the registry record. The number of listed outcomes alone does not show which were confirmatory or how results were intended to be interpreted.

The primary outcome is specified as complete TMA response through 26 weeks, and its analysis population is described as ITT. The registry information does not report the primary estimate, confidence interval, or any corresponding hypothesis test. It also does not report whether the secondary outcomes had prespecified analysis plans, whether any multiplicity adjustment was used, or how repeated measurements were handled for outcomes that change over time.

Missing-data methods and analysis-population details are not reported in the registry record. Although the primary tabulation is identified as ITT, the operational definition, analysis denominator, participant flow into the analysis, and rules for incomplete outcome measurements are absent from the information. In general, missingness can affect a responder outcome when participants lack measurements needed to verify each component or the required persistence of response. Without the handling rules and supporting counts, readers cannot assess whether missing data changed the classification of response or the precision of the estimate.

The record does not report interim analyses, stopping rules, or a statistical analysis plan. Their absence from the registry information should not be taken as evidence that such procedures were or were not used; they 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: device related sepsis (4.9%), pyelonephritis (4.9%), convulsion (4.9%), renal failure acute (4.9%), renal failure chronic (4.9%).

The registry safety summary lists 41 participants at risk for serious adverse events and 19 affected. For the other adverse-event category, it lists 41 at risk and 41 affected. These are registry-reported counts; the record information does not explain the category definitions or why the safety denominator differs from the enrollment of 44. It also does not report whether the safety population was defined differently from the primary-outcome ITT population.

The listed serious adverse-event terms are device related sepsis, pyelonephritis, convulsion, renal failure acute, renal failure chronic, and renal impairment, each recorded as 4.9%. The registry information does not specify whether these percentages refer to participants or events, or whether a participant could contribute to more than one term. The terms and percentages should not be added together to infer a total, because overlap and the percentage denominator are not reported.

These summaries describe reported adverse events, not necessarily events caused by eculizumab. The available information does not state how causality was assessed, how events were collected, or whether severity and seriousness were distinguished beyond the serious-event category. Deaths are not reported in the registry record; that does not establish that none occurred.

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

The record identifies a clinical question and a defined primary endpoint: complete TMA response through 26 weeks among adults with aHUS treated in a single-group eculizumab trial. It also specifies the response components and the planned method for estimating a responder proportion. However, the registry record does not report the primary response result or its confidence interval. The posted information therefore does not allow readers to determine the observed response frequency or its statistical precision.

Even if a response proportion were available, the single-group, open-label design would limit what it could establish. A proportion observed in the study group is not a direct comparison with outcomes under another treatment or no study treatment. Without a concurrent control group, differences attributable to treatment cannot be separated from other explanations using a randomized contrast. The record does not provide a basis for a causal treatment-effect estimate.

The endpoint’s combined hematologic and renal criteria and its requirement for sustained findings make its definition important to interpretation. The registry does not report component-level results, the number of participants in the primary analysis, or how missing measurements were handled. These omissions prevent a fuller assessment of how the composite was achieved and how incomplete follow-up may have affected classification.

The safety summary reports serious adverse events and selected terms, but its categories and percentage denominator are not fully described in the available information. The summary does not by itself establish causation. The registry does not report deaths. These limitations mean the safety information can be described as a record of reported events, but cannot support a complete causal assessment.

In general, statistical uncertainty and design uncertainty are different. A confidence interval can describe the precision of a numerical estimate under its method, while a control group and appropriate design are needed to support a comparative treatment-effect interpretation. Here, the primary estimate and interval are not reported, and the registered design is single-group. The registry record therefore supports a description of the study question and methods, but not a conclusion about the magnitude of a comparative treatment effect.

14. Why This Trial Matters Statistically

This trial illustrates why the registry’s design and endpoint definitions matter as much as the name of an outcome. Complete TMA response is not a single laboratory threshold: it combines platelet count and LDH normalization with a renal-function criterion, and requires the findings to persist across measurements. A reader needs that definition to understand what a responder proportion would represent. The registry states the definition but does not report the resulting proportion.

The design is also central to what can be learned. A single-group, open-label study can describe outcomes recorded among participants receiving the listed intervention, but does not supply a randomized comparison. This distinction helps prevent a response rate from being interpreted as a direct treatment effect. The registry record does not report a control group or a comparative estimate.

The record also highlights the importance of denominators and analysis populations. Enrollment is listed as 44, while the safety summary lists 41 at risk in each adverse-event category. The primary endpoint is said to use the ITT population, but its denominator is not reported. These figures serve different roles and should not be treated as interchangeable; the registry does not explain the difference.

Finally, the stated exact binomial confidence-interval method is useful information about how the primary responder rate was intended to be summarized. But a method description without the estimate and interval does not reveal the observed result or its precision. Statistical interpretation depends on both a clearly specified analysis and reported results, alongside an understanding of the design and limitations.

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 principal limitation for interpreting the primary outcome is that its result is not reported in the registry record. The response proportion and specified confidence interval are unavailable, so the frequency and precision of complete TMA response cannot be assessed. The primary analysis denominator is also not reported, despite the statement that tabulations used the ITT population.

The single-group design has no listed concurrent control, and masking is recorded as none. Consequently, the study description does not support a randomized comparison. The information available does not establish whether assessors were independently masked, or describe how open-label conduct may have influenced measurement or follow-up.

The registry does not report the detailed eligibility criteria, intervention dose or schedule, treatment duration, site-level analysis, or rules for participant discontinuation. It does not describe the handling of missing primary-outcome measurements, the operational definition of the ITT population, or the approach to multiplicity across the listed outcomes. These gaps make it difficult to assess reproducibility and the sensitivity of the findings to analysis choices.

The safety summary gives counts and selected serious-event terms, but the available information does not clarify the percentage denominator, potential overlap among terms, or event attribution. It also does not explain why the safety risk set differs from the recorded enrollment. Deaths are not reported in the registry record. These are reporting limitations and do not establish that an event did not occur or that an event was caused by treatment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open-label, Multi-center Clinical Trial of Eculizumab in Adult Patients With Atypical Hemolytic-uremic Syndrome — NCT01194973.
• Registry record last updated 2017-05-30; status last verified 2015-04.
• Results first posted 2015-04-24.
• 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

The registry describes a completed, phase 2, open-label, multicenter, single-group trial of eculizumab in adults with atypical hemolytic-uremic syndrome. Enrollment is recorded as 44; the start is 2010-07 and primary completion is 2013-10. The primary outcome was the percentage of participants with complete TMA response through 26 weeks, defined using hematologic normalization and renal-function preservation sustained across consecutive measurements.

The primary analysis was specified for the ITT population, with an exact binomial two-sided 95% Clopper-Pearson confidence interval. The primary response estimate and interval are not reported in the registry record. Safety listings report 19 affected among 41 at risk for serious adverse events and 41 affected among 41 at risk for the other adverse-event category. The listed serious-event terms each have a recorded percentage of 4.9%; deaths are not reported in the registry record.