A Study for Long-term Follow-up of Hemophagocytic Lymphohistiocytosis (HLH) Participants Who Received Treatment With Emapalumab (NI-0501), an Anti-interferon Gamma Monoclonal Antibody: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study for Long-term Follow-up of Hemophagocytic Lymphohistiocytosis (HLH) Participants Who Received Treatment With Emapalumab (NI-0501), an Anti-interferon Gamma Monoclonal Antibody (NCT02069899), a non-randomized phase 2, phase 3 study. The primary outcome is Number of Participants With Adverse Event (AE).

2. Clinical Question

This question concerns events observed during follow-up among people already exposed to emapalumab. It is not a randomized test of emapalumab against another treatment, and the design cannot isolate an effect of the drug from the underlying disease, prior care, transplantation, or other circumstances. The registry describes follow-up for up to 1 year after transplantation or the last emapalumab administration, with a maximum duration of 639 days. The endpoint therefore addresses the occurrence of events during a defined follow-up period, rather than a comparative treatment effect.

The enrolled population included people from Study NI-0501-04, Study NI-0501-06, and compassionate use. Those routes and their follow-up circumstances are clinically distinct. Results should be read as cohort-specific descriptions of this follow-up population, not as estimates applicable to a broader population or as evidence from a controlled comparison. The registry's primary endpoint is a participant count; it does not, by itself, describe event severity, duration, or attribution to emapalumab.

3. Trial Design

This was an international, multicenter, long-term follow-up study of participants with hemophagocytic lymphohistiocytosis who had received emapalumab previously. The registry lists Phase 2 and Phase 3, non-randomized allocation, no masking, and a parallel model. It records an enrollment of 58 participants and a completed status. The study start date was 2014-08-04, and primary completion was 2021-05-18.

The three cohorts were defined by prior emapalumab exposure. Participants in Enrolled-04 had taken part in Study NI-0501-04 and were invited for follow-up for 1 year after hematopoietic stem cell transplantation or the last emapalumab administration. Participants in Enrolled-06 had received at least 1 dose in Study NI-0501-06 and had been monitored for at least 4 weeks after the last administration; the registry describes an invitation to follow up for 1 year after that last administration. Enrolled-CU participants had received emapalumab under compassionate use. The registry describes compassionate use as an exceptional route for participants whose treating physician requested it after other possible treatment options had been exhausted and who could not enroll in a clinical study.

These cohorts do not constitute randomized arms. They differ in how participants entered follow-up and in the circumstances preceding enrollment. The registry explicitly cautions that the arms are not a like-for-like control comparison. Consequently, differences in observed events across cohorts should not be interpreted as treatment contrasts.

The primary endpoint counted participants with an adverse event from study enrollment through the specified follow-up period. The registry's definition includes any undesirable experience during the study, regardless of whether it was considered related to emapalumab. Secondary outcomes include response duration and overall survival in specified cohorts, as well as engraftment, donor chimerism, graft-versus-host disease, and MAS activity level. The registry lists 14 outcome measures. It reports no statistical analyses. Details beyond the cohort descriptions, including the complete protocol and procedures for analysis, 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who previously received treatment in a parent study (NI-0501-04 or NI-0501-06) or under compassionate use and who provided informed consent for participation in Study NI-0501-05.

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: Participants who previously received treatment in a parent study (NI-0501-04 or NI-0501-06) or under compassionate use and who provided informed consent for participation in Study NI-0501-05.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Event (AE), measured over From the date of enrollment in this study up to 1 year either after HSCT or after the last administration of emapalumab (maximum duration: 639 days).

The primary endpoint is the number of participants with an adverse event. It counts people who experienced at least one undesirable experience during the study, whether or not the event was considered related to emapalumab. The stated observation period runs from enrollment to 1 year after hematopoietic stem cell transplantation or the last emapalumab administration, with a maximum duration of 639 days.

A participant count is a straightforward way to describe how many people had an event during follow-up. It is distinct from a count of all event episodes: a participant with more than one event still contributes as a participant who experienced an event. The registry record does not provide a primary endpoint analysis or an overall primary endpoint result. It does list cohort-level safety counts for serious and other adverse events, but those figures should not be mistaken for a complete analysis of the primary endpoint unless the registry explicitly identifies them as such.

Including events regardless of judged treatment relationship gives a broad account of adverse experiences during observation. It does not establish that emapalumab caused an event. The endpoint also does not, on its own, convey the timing, duration, severity, or clinical consequences of each event. Those questions require event-level descriptions and analysis details, which are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a count of participants with an event. This is a binary participant-level concept: each participant either had at least one qualifying event during the observation period or did not. A count can describe the number of affected participants, while an event count would instead include repeated episodes in the same person. Those are different summaries. The registry's primary outcome is framed as participants, not as the total number of event episodes.

What does a confidence interval add?

In general, a confidence interval describes uncertainty around an estimated quantity under a statistical model. A narrow interval indicates greater precision than a wide interval, while neither guarantees that an estimate is free of bias. No confidence interval for the primary endpoint or the cohort safety counts is reported in the registry record. It is therefore not possible to assess precision from an interval estimate in the posted results.

Why does the study design matter?

Randomization can help make groups comparable, on average, for measured and unmeasured characteristics. This study is listed as non-randomized and has no masking. Its three cohorts reflect different prior-study or compassionate-use pathways, not assigned treatment groups. The registry cautions that the arms are not a like-for-like control comparison. Accordingly, contrasts between cohort counts would not have the interpretation of a randomized treatment effect.

In a follow-up study, observation time matters because participants may be followed for different lengths of time or under different conditions. The registry defines follow-up through 1 year after transplantation or last emapalumab administration, with a maximum duration of 639 days. It does not report an analysis using person-time, a time-to-event method for the primary safety endpoint, or a description of how incomplete follow-up was handled. A raw count does not adjust for variation in time at risk.

How should event percentages be read?

A percentage is interpretable only when its numerator and denominator are understood. The registry lists percentages for selected serious-event terms, but the denominator and relevant analysis details are not reported in the registry record. Those percentages should be quoted as listed, not used to infer unreported event counts or to make cohort comparisons. General statistical practice treats denominator clarity as essential for evaluating how common an event was.

Over-dispersion is a general issue for count data when variability exceeds what a simple count model would expect. It can make standard errors and intervals too optimistic if a model does not account for the extra variation. The registry does not report a count model, an assessment of over-dispersion, or a modeled event-rate analysis. Since the primary outcome is a participant count rather than a reported repeated-event rate, no such modeling claim can be made from the record.

What analyses are reported?

The registry lists 14 outcome measures and 0 analyses. No hypothesis tests, adjusted estimates, confidence intervals, or model specifications are reported. The absence of these details means that inferential claims cannot be evaluated from the registry record. It does not establish that no analyses were conducted elsewhere; it means the registry record does not report them.

The record includes planning assumptions for an illustrative sample-size calculation based on an observed effect: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the detectable effect expressed as a fraction of the observed effect. It specifies that time-to-event illustrations use total events under the Schoenfeld method and other illustrations use participants per arm. These are planning illustrations, not observed power and not evidence of the study's own design rationale. The trial-specific sample-size justification is not reported in the registry record. No sample-size illustration should be interpreted as a result observed in this follow-up study.

Multiplicity is a general concern when many outcomes or comparisons are tested, because the chance of at least one apparently notable finding can increase as tests accumulate. The registry lists multiple outcomes but reports no analyses or multiplicity procedure. It is therefore not possible to determine which outcomes were treated as primary for inferential testing beyond the named primary endpoint, whether testing was planned hierarchically, or whether any adjustment was made. No statistical plan, interim analysis details, or missing-data methods are reported in the registry record.

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("Enrolled-04 Cohort", "Enrolled-06 Cohort", "Enrolled-CU Cohort")
n      <- c(37, 14, 7)
events <- c(37, 12, 7)
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  Enrolled-04 Cohort  37  37  100.0  90.5  100.0  90.6  100.0  90.7  99.9
ARM  Enrolled-06 Cohort  14  12  85.7  57.2  98.2  60.1  96.0  59.5  95.7
ARM  Enrolled-CU Cohort  7  7  100.0  59.0  100.0  64.6  100.0  63.1  99.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including the primary adverse-event count and secondary outcomes that differ by cohort. It reports 0 analyses. A complete statistical plan, including any hierarchy among outcomes or adjustment for multiple testing, is not reported in the registry record. Because no inferential results are posted, there are no reported p-values or confidence intervals to assess for multiplicity.

In general, examining multiple outcomes can increase the chance of finding an apparently unusual result by chance if each is tested separately. Prespecified outcome hierarchies or multiplicity adjustments can address that issue, but the registry record does not state whether either approach was used. The list of outcomes alone does not establish how they were analyzed or prioritized.

The primary endpoint population is described as participants previously treated in a parent study or under compassionate use who provided informed consent for this follow-up study. Cohort-specific safety counts are reported, but detailed analysis-population definitions, participant disposition, and the handling of incomplete records are not reported in the registry record. Nor are missing-data assumptions, imputation methods, or sensitivity analyses described.

These omissions limit interpretation of the counts. If a participant's event information or follow-up were incomplete, the record does not explain how that circumstance affected inclusion in the reported figures. The registry also does not describe whether all outcomes were analyzed for all cohorts or how denominators were selected for each outcome. These points should remain unresolved rather than being inferred from the available cohort totals.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: condition aggravated (28.6%), pseudomonal sepsis (28.6%), pyrexia (16.2%), vomiting (14.3%), septic shock (14.3%).

The registry reports serious and other adverse-event counts by cohort. In Enrolled-04, serious events affected 28 of 37 participants and other events affected 37 of 37; 9 deaths are listed. In Enrolled-06, serious events affected 3 of 14 and other events affected 11 of 14; 0 deaths are listed. In Enrolled-CU, serious events affected 6 of 7 and other events affected 7 of 7; 2 deaths are listed.

These are descriptive counts within distinct cohorts. The cohorts were not randomized against each other, and the registry cautions that they are not like-for-like control arms. The numbers therefore do not establish that one cohort had greater or lesser risk because of emapalumab or any other factor. Differences in cohort size and follow-up circumstances also matter, and the registry does not provide a comparative analysis that adjusts for them.

The listed serious-event terms include Condition aggravated and Pseudomonal sepsis, each reported as 28.6%; Pyrexia at 16.2%; and Vomiting, Septic shock, and Klebsiella sepsis, each at 14.3%. The denominator and analysis details for these term percentages are not reported in the registry record. Serious-event counts, other-event counts, selected term percentages, and deaths are distinct summaries and should not be combined into a single measure.

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

The posted results describe safety observations during long-term follow-up of participants who had previously received emapalumab. The registry gives cohort-level counts of participants affected by serious and other adverse events and lists deaths. These data provide a descriptive account of events recorded in this follow-up population. They do not provide a controlled comparison between emapalumab and another treatment, because the study was non-randomized and no comparator group is described.

The primary endpoint is broad: it counts any undesirable experience during the study, regardless of whether it was considered related to emapalumab. This helps define what the endpoint intends to capture, but it does not establish cause. The registry record does not provide an overall primary endpoint analysis, an estimate of the treatment effect, confidence intervals, or hypothesis tests. The cohort safety figures should not be treated as substitutes for those missing results.

The figures also do not answer every question about safety. Counts do not describe the timing or duration of events, the number of repeated events per participant, or the full clinical context. Although selected serious-event terms and percentages are listed, the record does not state the denominator or analysis details for those percentages. The listed death counts are not accompanied by causes or a comparative mortality analysis.

The record describes follow-up after prior treatment, transplantation, or compassionate use, depending on cohort. These differing circumstances can affect how observations are interpreted. The study does not separate the contribution of prior emapalumab exposure from disease, transplantation, other care, or other influences. Its results therefore cannot establish that emapalumab caused or prevented an event, nor can they establish a comparative benefit or harm.

In general, a non-randomized follow-up study can be useful for describing what was recorded among enrolled participants over time. The registry record supports that limited descriptive interpretation. It does not report enough statistical detail to judge precision, missing-data effects, or the extent to which the enrolled participants represent people outside these cohorts. Conclusions should stay within the population, follow-up conditions, and reported outcomes described in the record.

14. Why This Trial Matters Statistically

This study is statistically distinctive because it follows participants after prior emapalumab exposure rather than assigning participants to a new treatment comparison. That design changes the question the data can answer. The cohort-level safety observations describe events among enrolled participants, but they do not estimate a randomized contrast or isolate the effect of emapalumab.

The three cohorts also reflect different routes into follow-up: participation in Study NI-0501-04, participation in Study NI-0501-06, or compassionate use. Keeping those cohorts distinct is important. Their counts should not be pooled or compared as though the groups had been formed by random assignment. The registry itself cautions that the arms are not a like-for-like control comparison.

The study also highlights a basic distinction between a broad safety endpoint and causal attribution. The primary outcome counts adverse events whether or not considered related to emapalumab. That definition records experiences during observation, but it cannot determine what caused them. Clear endpoint definitions are essential for understanding what a number represents and what it leaves unanswered.

Finally, the registry's record of 14 outcome measures and 0 analyses illustrates why design information and reported analysis details matter. Without estimates, uncertainty intervals, analysis populations, and missing-data methods, readers cannot judge precision or inferential strength from counts alone. The results remain useful as descriptive follow-up information, but their statistical meaning is bounded by the non-randomized design and the limited analysis reporting.

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 is the absence of a randomized comparator. The study is non-randomized, and its cohorts come from different prior-treatment or compassionate-use settings. The registry explicitly states that the arms are not a like-for-like control comparison. Cohort differences therefore cannot be interpreted as evidence of relative treatment effects.

The registry reports no analyses, although it lists 14 outcome measures. No confidence intervals, hypothesis tests, adjusted estimates, or statistical model details are reported. The primary endpoint is named and defined, but an overall primary endpoint result is not reported in the registry record. The record also does not describe a statistical analysis plan, multiplicity procedure, interim analyses, or a trial-specific sample-size justification.

Follow-up is described as extending to 1 year after transplantation or the last emapalumab administration, with a maximum duration of 639 days. The registry does not report how differences in observation time were handled analytically, how incomplete follow-up or missing outcome data were treated, or whether sensitivity analyses were conducted. The denominator and analysis details for the listed serious-event term percentages are also not reported.

The safety counts are descriptive and cannot establish event causation. The adverse-event definition includes experiences regardless of whether they were considered related to emapalumab, while the registry does not provide an attribution analysis. Counts also do not describe repeated events, timing, or event duration. Finally, the enrollment of 58 does not by itself establish how many participants contributed to every outcome or analysis; detailed participant disposition by outcome is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study for Long-term Follow-up of Hemophagocytic Lymphohistiocytosis (HLH) Participants Who Received Treatment With Emapalumab (NI-0501), an Anti-interferon Gamma Monoclonal Antibody — NCT02069899.
• Registry record last updated 2022-06-28; status last verified 2022-05.
• Results first posted 2022-06-28.
• 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

NCT02069899 is a completed, international, multicenter, non-randomized, unmasked, parallel long-term follow-up study of participants with hemophagocytic lymphohistiocytosis who had previously received emapalumab. The registry lists Phase 2 and Phase 3 and an enrollment of 58. The study began on 2014-08-04, with primary completion on 2021-05-18.

Participants entered through Enrolled-04, Enrolled-06, or Enrolled-CU cohorts. The primary endpoint was the number of participants with an adverse event during the defined follow-up period, regardless of whether the event was considered related to emapalumab. Cohort-level counts of serious and other adverse events and deaths are reported. The registry lists 14 outcome measures and 0 analyses; an overall primary endpoint analysis and statistical analysis details are not reported in the registry record.