Follow-up Study for Patients Who Completed Study ALX0681-C301 (Post-HERCULES): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Follow-up Study for Patients Who Completed Study ALX0681-C301 (Post-HERCULES) (NCT02878603), a na phase 3 study. The primary outcome is Percentage of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Related Events.

2. Clinical Question

The study was designed to evaluate long-term safety and efficacy of caplacizumab, the safety and efficacy of repeated caplacizumab use, and the long-term impact of aTTP. These are the objectives recorded for the follow-up; they should not be mistaken for findings. The registry record does not report the primary endpoint percentage, a treatment-effect estimate, or a statistical comparison for that endpoint.

The follow-up is not a like-for-like comparison of two newly assigned treatments. Participants entered after completing C301, and the safety categories describe treatment received in that earlier study. Their outcomes may reflect the course of aTTP, prior treatment, and events during follow-up. The registry record does not provide a randomized contrast that would separate those influences from a treatment effect.

3. Trial Design

NCT02878603, titled “Follow-up Study for Patients Who Completed Study ALX0681-C301 (Post-HERCULES),” is listed as a phase 3, completed study. It was prospective, had no masking, and used a single-group model. Allocation is listed as not applicable. Enrollment is recorded as 104. The study start date is 2016-10-06 and primary completion is recorded as 2020-10-23.

Participants had completed ALX0681-C301, also known as HERCULES, before enrolling in the follow-up. The registry describes C301 participants as having received standard of care, including plasma exchange, corticosteroid and other immunosuppressive agents, or caplacizumab with plasma exchange and immunosuppressive agents. The arm description in the registry record is incomplete, so further details about follow-up treatment rules should not be inferred from it.

The primary endpoint was the percentage of participants with aTTP-related events from baseline up to 36 months. Its efficacy intention-to-observe population included participants enrolled in LTS16371 who had not experienced an aTTP recurrence in C301 or before the beginning of LTS16371. The registry lists 23 outcome measures, but no analysis entries. The endpoint result and its uncertainty are not reported in the registry record.

The two safety groups are labeled by C301 treatment: standard of care and caplacizumab. Their records list 29 and 75 participants at risk for serious adverse events, respectively. These categories describe prior-study treatment, not randomized treatment assignments in the follow-up. Accordingly, differences between the categories cannot be read as causal effects of caplacizumab. The registry record does not report a protocol-level statistical plan, the reasons for the enrollment target, or further detail about how follow-up observations were analyzed.

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: Participants who were randomized to caplacizumab/placebo and received caplacizumab for recurrence of acquired thrombotic thrombocytopenic purpura (aTTP) in ALX0681-C301 were enrolled in Caplacizumab group, and participants randomized to placebo in ALX0681-C301 were enrolled under Standard of Care (SoC) group in the current study LTS16371.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on efficacy intention-to-observe (efficacy ITO) population which included participants who were enrolled in LTS16371 and did not experience an aTTP recurrence in previous study ALX0681-C301 or prior to the beginning of LTS16371.

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: Analyzed on overall intention-to-observe (overall ITO) population which included participants who were enrolled in LTS16371, grouped by whether they received caplacizumab during previous study ALX0681-C301 versus those who never received caplacizumab before enrollment in LTS16371.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Related Events, measured over From Baseline up to 36 months.

The primary endpoint is a participant-level measure: the percentage of the specified efficacy population with at least one aTTP-related event during follow-up from baseline up to 36 months. The event definition includes aTTP-related death, a recurrence of aTTP defined by recurrent thrombocytopenia requiring initiation of daily plasma exchange, or at least one major thromboembolic event. Examples listed in the registry are myocardial infarction, cerebrovascular accident, pulmonary embolism, and deep venous thrombosis.

This composite endpoint brings together events that reflect serious consequences of aTTP, but its components are not interchangeable. A participant can meet the endpoint through different types of events, and the percentage alone would not show which component drove the result. Component-specific counts and timing would help characterize the clinical pattern, but are not reported in the registry record for this primary endpoint.

General statistical context: a percentage with an event expresses how common the defined outcome was in the analysis population over the stated observation period. It is not a rate per unit of person-time, and it does not by itself describe when an event occurred. Interpretation also depends on the population used, the completeness of follow-up, and the precise event definitions. The registry record supplies the endpoint definition and population criteria but does not report the observed percentage or an uncertainty interval. Therefore, the endpoint’s observed frequency and precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint summarize?

The endpoint is a percentage of participants meeting a composite definition, rather than a continuous measurement or a time-to-event estimate. Meeting the definition requires at least one of the specified events during the stated follow-up period. The components are aTTP-related death, recurrence requiring initiation of daily plasma exchange, or a major thromboembolic event. Because each component can qualify a participant, the composite summarizes whether any qualifying event occurred, not the number of events or their severity ranking.

General statistical context: composite outcomes can capture a broader range of clinically important events, but their interpretation depends on the components. A result can be driven by a more frequent component even when less frequent components are severe. Component-level reporting helps readers understand that balance. The registry record defines the composite but does not report the primary endpoint result or component breakdown.

What does an event percentage mean?

General statistical context: a participant percentage is calculated relative to a defined analysis population. The meaning of the estimate depends on who is included and whether participants had comparable opportunity for observation. The primary population excludes participants with a recurrence during C301 or before LTS16371 began. That restriction is part of the endpoint’s stated population, and the result would apply to that defined group rather than automatically to everyone with aTTP or everyone completing C301.

The endpoint timeframe is from baseline up to 36 months. The registry record does not report the observed percentage, the number of participants contributing to the primary analysis, or an uncertainty interval. It also does not give further details about censoring, loss to follow-up, or how differing observation time was addressed. Those omissions prevent a fuller evaluation of the estimate’s precision and representativeness.

How should uncertainty be understood?

General statistical context: a confidence interval conveys sampling uncertainty around an estimate under specified assumptions. A narrower interval indicates greater precision under those assumptions; it does not establish that the study design is free of bias. An interval for a participant percentage would be useful alongside the observed percentage, especially when the event is uncommon or the analyzed population is limited. The registry record does not report a confidence interval for the primary endpoint.

A p-value, if reported, would address compatibility of data with a specified null hypothesis under the analysis model. It would not measure the probability that a treatment works, nor would it tell readers whether an observed difference is important. No primary endpoint p-value or comparative test is reported in the registry record.

What do the planning assumptions mean?

General statistical context: the registry information about sample-size planning describes an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes detecting a stated fraction of the observed effect. Such illustrations are planning calculations, not observed outcomes and not observed power. The registry record does not report the observed primary effect or the numerical planning results, so the assumptions cannot be used to infer the study’s achieved precision or its ability to detect an effect.

The assumptions also describe a two-arm equal-allocation framework, whereas this follow-up is recorded as a single-group study with allocation not applicable. A planning illustration based on two arms should not be mistaken for the actual design or for evidence that this follow-up made a randomized comparison. The registry record does not report a formal sample-size justification for the study.

What can the safety counts show?

The safety entries give the numbers at risk and the numbers affected for serious and other adverse events, organized by C301 treatment category. These are descriptive counts. The registry record does not provide inferential comparisons, adjustment for differences between the categories, or an analysis specifying how repeated events were handled. The counts therefore describe reported experience in the listed groups but do not quantify a causal effect.

General statistical context: simple counts do not fully describe event burden when participants may experience multiple events or when observation time varies. A participant-level measure of whether an event occurred differs from an event count, and both differ from an event rate that accounts for time at risk. The registry record does not provide enough detail to reconstruct those other measures. Interpret the serious-event terms as listed categories and percentages, not as mutually exclusive contributions to a total.

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("Standard of Care (SoC) (Treated in Study C301)", "Caplacizumab (Treated in Study C301)")
n      <- c(29, 49)
events <- c(11, 4)
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  Standard of Care (SoC) (Treated in Study C301)  29  11  37.9  20.7  57.7  22.7  56.0  22.7  56.1
ARM  Caplacizumab (Treated in Study C301)  49  4  8.2  2.3  19.6  3.2  19.2  3.3  19.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 23 outcome measures and no analysis entries. It does not report a statistical analysis plan describing which endpoints were primary, secondary, or exploratory for purposes of hypothesis testing, nor does it describe any adjustment for multiple testing. Without those details, the consequences of testing or interpreting multiple outcomes cannot be assessed. The primary endpoint is identified in the record, but no inferential result for it is reported.

Missing-data handling is not reported in the registry record. In particular, the record does not explain how missed visits, withdrawal, incomplete event ascertainment, or varying follow-up were handled for the primary percentage. This matters because an endpoint based on whether a participant experienced an event can be affected by how completely events are observed. No assumptions about missingness or imputation should be attributed to the study without documentation.

The primary efficacy population is defined as participants enrolled in LTS16371 who had not experienced an aTTP recurrence in C301 or before the start of LTS16371. The registry record does not report the analyzed population size for this endpoint or any additional exclusions. The safety counts are presented for groups defined by treatment in C301; that grouping should not be confused with the primary endpoint population or with randomized assignment in the follow-up.

General statistical context: multiplicity concerns arise when several outcomes or analyses are examined, because chance findings can become more likely across repeated tests. Missing-data methods can also affect estimates, and conclusions depend on assumptions about why observations are absent. Since the registry record does not report the relevant analysis procedures, neither issue can be resolved from the posted information.

12. 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: thrombotic thrombocytopenic purpura (27.6%), back pain (6.9%), acute myocardial infarction (3.4%), angina unstable (3.4%), pericarditis (3.4%).

The serious adverse-event entries are grouped by treatment received in C301. The standard-of-care group lists 29 participants at risk and 16 affected; the caplacizumab group lists 75 at risk and 28 affected. The death counts are 1 and 0, respectively. The other-adverse-event counts list 22 affected among 29 at risk in the standard-of-care group, and 58 among 75 at risk in the caplacizumab group.

The serious-event terms listed include thrombotic thrombocytopenic purpura (27.6%), back pain (6.9%), and acute myocardial infarction, unstable angina, pericarditis, and migraine (each 3.4%). The registry record does not specify treatment attribution alongside these term percentages. They should be read as reported term frequencies, not interpreted as evidence of a treatment effect.

These entries are descriptive and do not establish that treatment caused or prevented an event. The groups reflect earlier C301 treatment, and the record does not report a randomized comparison or adjustment for group differences. It also does not state whether participants could contribute multiple adverse-event terms or how event timing and exposure duration were handled. Do not add term percentages or treat them as a breakdown of mutually exclusive outcomes.

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

The study is a prospective follow-up of participants who completed HERCULES. Its stated purpose was to examine longer-term safety and efficacy of caplacizumab, repeated use of caplacizumab, and the impact of aTTP over time. The primary endpoint was defined as the percentage of the specified efficacy population with at least one aTTP-related event from baseline up to 36 months.

That definition gives readers a clear account of the outcome the registry intended to assess, and the record provides selected safety counts by prior C301 treatment category. However, the primary endpoint result is not reported in the registry record. There is no posted estimate or uncertainty interval from which to judge the frequency of the composite outcome or how precisely it was measured. The objectives and endpoint definition alone do not show whether an outcome was common or uncommon.

The safety counts are not a causal comparison. Participants were not randomized between the listed categories in this follow-up; those categories refer to treatment received in C301. Any differences could reflect participant characteristics, disease history, earlier treatment, or other factors. The available information does not isolate the contribution of a particular treatment to later outcomes.

General statistical context: a follow-up study can describe outcomes after an earlier trial and can provide information about events occurring over a longer period. Its conclusions still depend on who enters follow-up, how outcomes are collected, how long participants are observed, and how missing observations are treated. The registry record does not report enough analytic detail to evaluate all of those considerations.

Consequently, the posted information supports a description of the study question, design, primary endpoint definition, and selected safety experience. It does not establish comparative efficacy, an effect of repeated caplacizumab use, or the absence of risk. Nor does the absence of a reported primary result mean that no events occurred. The registry record simply does not report that endpoint result.

14. Why This Trial Matters Statistically

This study is statistically notable as a prospective extension following a phase 3 trial, with a focus on outcomes beyond the earlier study. Long-term follow-up can address questions that a shorter observation period may leave open, including whether disease-related events and safety concerns continue to be observed after the original trial. The registry states these aims but does not provide the primary efficacy result.

The endpoint definition also illustrates an important issue in clinical-trial interpretation: a composite combines distinct events into a participant-level summary. A composite can be useful when several outcomes are relevant to the research question, but readers need the result for the overall endpoint and ideally its components to understand what the measure represents in practice. In this record, the definition is available, while the observed primary percentage and component results are not reported.

The study further demonstrates why design labels and group labels matter. Although safety counts are divided by treatment received in C301, this follow-up is described as single-group with allocation not applicable. The earlier treatment categories are not equivalent to randomized arms created in the follow-up. Recognizing that distinction prevents descriptive counts from being mistaken for evidence of comparative treatment effects.

Finally, the record illustrates how a registry entry can contain study objectives, outcome definitions, and safety counts without enough information to evaluate the primary result statistically. The absence of analysis entries and the lack of reported uncertainty or missing-data procedures leave important questions unresolved. For biostatisticians and clinical researchers, separating what the design intended to measure from what the posted results actually establish is essential.

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 registry record does not report the primary endpoint estimate, its uncertainty, or an analysis result. That is the central limitation for evaluating the study’s stated efficacy question. Although the endpoint definition and follow-up timeframe are available, they cannot reveal the observed frequency of aTTP-related events.

The design is listed as single-group, with no masking and allocation not applicable. Safety group labels are based on C301 treatment rather than assignment in the follow-up, so they do not provide a randomized comparison. The registry record does not report adjustment for differences between these categories or information that would support causal interpretation.

The primary analysis population excludes participants with a recurrence during C301 or before LTS16371 began. The registry record does not report the size of that population or the number contributing to the primary analysis. This limits assessment of how the endpoint population relates to enrollment and of the precision that might be expected.

Details about missing data, loss to follow-up, event adjudication, follow-up duration by participant, and handling of repeated events are not reported in the registry record. The record also does not provide the statistical analysis plan, multiplicity procedures, or a formal sample-size justification. The arm description is incomplete, limiting what can be established about follow-up treatment procedures.

The listed adverse-event counts and term percentages are descriptive. The registry record does not provide treatment attribution for the serious-event term percentages, comparative analyses, or sufficient information to determine whether terms overlap. These limitations restrict interpretation of safety patterns and prevent using the counts to infer treatment-related risk.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Follow-up Study for Patients Who Completed Study ALX0681-C301 (Post-HERCULES) — NCT02878603.
• Registry record last updated 2022-03-28; status last verified 2022-03.
• Results first posted 2021-11-22.
• 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

NCT02878603 is a completed, prospective, phase 3 follow-up study of participants who completed ALX0681-C301 (HERCULES). The registry lists enrollment as 104, a single-group model, no masking, and allocation not applicable. The study start date is 2016-10-06; primary completion is 2020-10-23.

The stated objectives were to evaluate long-term safety and efficacy of caplacizumab, repeated use of caplacizumab, and the long-term impact of aTTP. The primary endpoint was the percentage of the efficacy intention-to-observe population with at least one aTTP-related event from baseline up to 36 months. The registry lists 23 outcome measures and no analysis entries. The primary endpoint result and its uncertainty are not reported in the registry record.

Safety counts are categorized by treatment received in C301. They are descriptive and do not constitute a randomized comparison within the follow-up study.