Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS) (NCT03131219), a non-randomized phase 3 study. The primary outcome is Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26.

2. Clinical Question

3. Trial Design

This was a Phase 3, open-label, multicenter, non-randomized, single-group study of ravulizumab in children and adolescents with aHUS. The registry lists an enrollment of 34 and a completed status. The study start date is 2017-08-31, and the primary completion date is 2022-12-20. Those dates describe the registry record and do not, by themselves, establish the timing of every analysis or follow-up activity.

The study purpose included two participant histories: complement inhibitor treatment-naïve participants and adolescent participants previously treated with eculizumab. The primary endpoint was specifically defined for the treatment-naïve participants. The reported safety groups likewise distinguish treatment-naïve participants from eculizumab-experienced participants. Because allocation was non-randomized and there was no control group, the two histories do not form a randomized comparison. Differences between them could not be interpreted as an effect of prior treatment or as a controlled estimate of ravulizumab’s effect.

Participants received ravulizumab in an initial evaluation period of 26 weeks. The registry describes weight-based dosing and different dosing intervals depending on weight. The dosing description after the initial evaluation period is truncated in the registry record, so the later treatment schedule is not reported in the registry record in full. The primary response was evaluated at Week 26. Listed secondary outcomes include response at Week 52, time to complete TMA response, dialysis status, kidney-function measures, CKD stage, platelet count, LDH, and hemoglobin.

The registry states that formal statistical comparison analyses were not planned. It does not report a randomized comparator, a sample-size justification, or a statistical plan for comparative treatment effects. The record’s design therefore supports a descriptive reading of the recorded outcomes, not a controlled causal 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.

Initial Evaluation Period

Reasons for not completing this period:

Extension Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, and met pre-specified eligibility criteria. Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure.

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: All participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26, measured over Week 26.

The primary endpoint was the percentage of complement inhibitor treatment-naïve participants with complete thrombotic microangiopathy (TMA) response at Week 26. TMA response combines findings from blood measures and kidney function: the endpoint required normalization of platelet count and lactate dehydrogenase (LDH), plus improvement in kidney function defined as a reduction in serum creatinine of at least 25% from baseline. For participants receiving dialysis, the registry specifies how baseline was established in relation to the end of dialysis.

The definition also requires persistence across time rather than a single qualifying measurement. Participants had to meet the criteria at two separate assessments at least 4 weeks (28 days) apart, with any measurement in between. To qualify during the initial evaluation period, the latest first qualifying time point had to be 28 days before the Week 26 (Day 183) assessment.

A composite endpoint can represent several clinically relevant dimensions in one outcome, but its interpretation depends on every component and timing rule being met. A participant who does not meet one required component does not meet the composite definition, even if other components improve. The registry specifies an exact Clopper Pearson confidence interval for the percentage. However, it does not report the primary response count, percentage, or confidence limits. The endpoint’s observed result is therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

The primary outcome is a percentage of participants meeting a binary definition. Each participant is classified as having or not having complete TMA response by Week 26 under the stated criteria. A percentage describes the observed frequency of responders in the analyzed group; it does not, by itself, describe the size of a treatment effect relative to another group. The registry does not report the numerator, denominator, or resulting percentage for this endpoint, so no numerical estimate can be interpreted.

Why is the endpoint composite?

As a general statistical concept, a composite endpoint combines multiple required measures into one participant-level outcome. In this study, complete response requires normalization of platelet count and LDH and kidney-function improvement. This can capture more than one dimension of disease activity in a single outcome, but interpretation depends on the full definition: a participant must satisfy all of its required elements. A composite result would not reveal the separate contribution of each component unless component-specific results were also reported. Those component-specific primary results are not reported in the registry record.

What role do repeated assessments play?

The registry requires qualifying findings at two separate assessments at least 4 weeks (28 days) apart, with any measurement in between, and restricts how late the first qualifying time point may occur. These rules make the endpoint depend on both the measurements and their timing. In general, requiring confirmation can distinguish a sustained pattern from a single qualifying observation, while also making the definition more demanding than a one-time threshold. The record does not give participant-level assessment histories or explain how incomplete measurement sequences were handled.

What does the confidence interval tell a reader?

The registry states that the percentage’s confidence interval is based on exact Clopper Pearson confidence limits. In general, a confidence interval describes uncertainty around an estimate under the assumptions of the statistical procedure. It is not a guarantee that the true value lies within a particular interval, nor does it measure bias from study design or missing observations. An exact interval is a method for estimating uncertainty for a binomial proportion, especially when the amount of information is limited; its use does not overcome the lack of a randomized comparator. The interval limits themselves are not reported in the registry record.

Why does the design matter for interpretation?

In a randomized controlled comparison, assignment can support a between-group estimate under the study’s design and analysis assumptions. Here, allocation is non-randomized, masking is none, and the model is single-group. The registry states that formal statistical comparison analyses were not planned. As a general principle, an observed within-group outcome cannot by itself separate treatment effects from other influences. Open-label assessment can also be relevant to outcomes involving clinical judgments or timing, although the primary endpoint includes laboratory and kidney-function criteria. The record does not describe blinded outcome assessment.

What is over-dispersion, and is it relevant to this endpoint?

Over-dispersion is a general issue for models of count or proportion data when the observed variability exceeds what the chosen model assumes. It can make standard errors too small if ignored. The registry describes an exact confidence-interval method for the primary percentage, not a regression model or an over-dispersion adjustment. The record therefore does not report an over-dispersion analysis for this endpoint. The concept should not be mistaken for a reported study finding.

How should planning illustrations be understood?

Sample-size illustrations based on an observed effect are planning exercises, not evidence about how many participants were actually enrolled or how likely the completed study was to detect an effect. In general, such illustrations depend on stated assumptions, including significance level, allocation, and the effect chosen for detection. The registry record says formal statistical comparison analyses were not planned, and it does not report a sample-size justification. No planning result should be interpreted as observed power or as a trial outcome.

What can be concluded from the listed analysis population?

The Full Analysis Set is described as participants who received at least 1 dose, had at least 1 post-baseline efficacy assessment, and met pre-specified eligibility criteria. The endpoint description clarifies that the number analyzed signifies participants evaluable for that outcome. These definitions identify eligibility conditions for inclusion, but do not provide the actual number analyzed. In general, excluding participants without post-baseline assessments can affect how representative the analyzed group is of all enrolled participants. The registry does not report reasons for exclusions or the handling of missing endpoint data.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and several secondary outcomes, including time to complete TMA response, response at Week 52, dialysis status, eGFR, CKD stage, platelet count, LDH, and hemoglobin. It reports 11 outcome measures. The fact that multiple outcomes are listed raises a general multiplicity consideration: when many hypotheses are assessed, the chance of at least one apparently notable finding can increase if results are interpreted without an appropriate plan. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes. It does state that formal statistical comparison analyses were not planned.

The primary endpoint’s description specifies the Full Analysis Set eligibility criteria and says that the number analyzed is the number evaluable for that endpoint. It does not give the actual endpoint denominator or the number of participants excluded from that analysis. The registry record also does not report a missing-data method, imputation procedure, sensitivity analysis, or reasons for absent measurements. The handling of participants who did not complete assessments needed to establish the required response timing is not reported in the registry record.

These omissions matter because a percentage depends on both the responder count and the population used as its denominator. As a general point, results can be sensitive to how missing outcomes and exclusions are handled, particularly when missingness is related to health status or study participation. Without the analysis denominator and missing-data approach, that sensitivity cannot be evaluated. No missing-data assumption should be inferred from the endpoint definition alone.

The record defines the outcome population but does not report the associated result. Thus, neither multiplicity-adjusted interpretation nor a detailed appraisal of missingness is possible from the registry information. The outcomes listed are not numerical findings, and their presence in the registry does not establish that results were analyzed or reported.

11. Safety Results

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

Deaths

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: pyrexia (16.7%), diarrhoea (12.5%), bronchitis (10.0%), pneumonia (10.0%), upper respiratory tract infection (10.0%).

The safety figures distinguish complement inhibitor treatment-naïve participants from eculizumab-experienced participants. In the treatment-naïve group, 24 participants were at risk for serious adverse events and 16 were affected; for other adverse events, 24 were at risk and 21 were affected. In the eculizumab-experienced group, 10 were at risk for serious adverse events and 1 was affected; for other adverse events, 10 were at risk and 10 were affected. The record lists 0 deaths in each group.

These are counts of participants, not counts of every event episode. The registry’s listed serious adverse-event terms include Pyrexia (16.7%), Diarrhoea (12.5%), Bronchitis (10.0%), Pneumonia (10.0%), Upper respiratory tract infection (10.0%), and Gastroenteritis viral (8.3%). These terms and percentages are descriptive entries; the registry information does not establish that ravulizumab caused them. The figures should not be compared as if the two groups were randomized or equivalent in baseline characteristics. The meaning of the separate “other” category beyond its label is not reported in the registry record. Safety counts also do not substitute for the missing primary efficacy result.

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

The record establishes that a Phase 3 study of ravulizumab was completed in children and adolescents with aHUS and describes a Week 26 complete TMA response endpoint for complement inhibitor treatment-naïve participants. It also defines the response criteria, identifies an exact confidence-interval method, lists other outcomes, and reports adverse-event counts by treatment history group. These elements explain what the study set out to assess and how some outcomes were framed.

The record does not report the Week 26 primary response count, percentage, denominator, or confidence interval. It therefore does not show the observed frequency or precision of complete response. This absence must not be read as no participants responding, as a zero result, or as evidence for no effect. The secondary outcome results also are not reported in the registry record in the registry record for this analysis.

Even if an uncontrolled study reports a within-group response, such a result is not equivalent to a randomized treatment comparison. General statistical interpretation requires distinguishing an observed outcome during treatment from an estimate of what would have happened under a comparator. Since this study has no randomized control group and formal statistical comparison analyses were not planned, the registry design cannot provide that controlled contrast.

The adverse-event counts describe participants with events in the two treatment-history groups, and the record reports zero deaths in each. They do not establish causation, nor do the group counts establish comparative safety between equivalent groups. The registry record does not report additional details needed to judge event duration, severity beyond the serious-event classification, attribution, or exposure-adjusted rates.

Accordingly, the defensible reading is limited: the registry gives a study design and prespecified outcome definitions, along with descriptive safety counts, but does not provide the primary efficacy result. The study’s importance or clinical implications cannot be inferred from the endpoint definition or design alone. Any conclusion about response magnitude, uncertainty, or comparative effect would require results not reported in the registry record.

13. Why This Trial Matters Statistically

Statistically, this trial is a useful example of why endpoint definitions and outcome estimates must be read separately. The registry describes a demanding composite response definition with laboratory and kidney-function criteria and repeated assessments over time. That level of detail helps clarify what a responder would mean. Yet a detailed definition cannot replace the actual responder count, denominator, and uncertainty interval. Those primary results are not reported in the registry record.

The study also illustrates the limits of a single-group, non-randomized design. A within-group percentage, if reported, would describe the participants observed under study conditions. Without random allocation to a comparator, it would not isolate the effect of ravulizumab from other influences. The registry explicitly says that formal statistical comparison analyses were not planned. That is an important boundary on the kinds of claims the design can support.

Several design details are relevant to statistical reading: the primary endpoint applies to treatment-naïve participants, while the study purpose also includes eculizumab-experienced adolescents; the analysis population has eligibility requirements; and the endpoint requires multiple assessments. These choices shape both who contributes to the estimate and what qualifies as a response. The actual endpoint-specific population size and missing-data handling are not reported in the registry record, so readers cannot assess those aspects empirically.

The safety information reinforces the distinction between descriptive reporting and comparative inference. Counts are given by treatment history, but those groups are not randomized comparison arms. Their figures can describe the record’s reported events without establishing causation or a difference in underlying risk. Taken together, these features make the trial statistically informative as an example of what registry design and endpoint descriptions can establish—and what they cannot establish in the absence of reported efficacy estimates.

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.

A central limitation for interpreting the posted information is that the primary endpoint result is not reported in the registry record. Without the response count, analysis denominator, percentage, or confidence limits, neither the observed response frequency nor its precision can be assessed. The overall enrollment of 34 does not resolve this gap, because it is not necessarily the number evaluable for the treatment-naïve primary endpoint.

The study was open-label, non-randomized, and single-group. There was no randomized control group, and the registry states that formal statistical comparison analyses were not planned. The treatment-naïve and eculizumab-experienced groups represent different treatment histories, not randomized arms; differences between their outcomes would not establish a comparative treatment effect. The record also does not report blinded outcome assessment.

The primary endpoint is a composite requiring several criteria and repeated measurements. Although the registry defines these requirements, it does not provide component-level outcomes or participant-level assessment patterns. It also does not report how missing measurements, incomplete follow-up, or participants not evaluable for the endpoint were handled. These details limit assessment of potential selection and missing-data effects.

The registry lists multiple secondary outcomes but does not report their numerical results in the registry record for this analysis. It does not report a multiplicity plan, sample-size justification, or interim-analysis plan. These details are not reported in the registry record and should not be inferred. The safety counts are descriptive, with no exposure-adjusted rates or attribution details. Finally, the dosing description after the initial evaluation period is incomplete in the registry record. These limits constrain interpretation without establishing that any particular result was favorable or unfavorable.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS) — NCT03131219.
• Registry record last updated 2024-03-15; status last verified 2024-03.
• Results first posted 2020-09-16.
• 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

This completed Phase 3 study evaluated ravulizumab in children and adolescents with aHUS. It was open-label, non-randomized, and single-group, with enrollment of 34. Its primary endpoint was the percentage of complement inhibitor treatment-naïve participants with complete TMA response at Week 26, defined by hematological normalization, kidney-function improvement, and repeated qualifying assessments. The registry specifies an exact Clopper Pearson confidence interval but does not report the primary endpoint result or its denominator.

The record lists secondary outcomes and descriptive adverse-event counts for treatment-naïve and eculizumab-experienced groups, including zero deaths in each. Because there was no randomized comparator, those groups are not like-for-like control arms. Missing-data handling, multiplicity methods, sample-size justification, and detailed comparative analyses are not reported in the registry record. The posted information therefore describes the study structure and endpoint but does not provide a numerical efficacy estimate.