Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency (NCT01371825), a na phase 2, phase 3 study. The primary outcome is Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age.

2. Clinical Question

The study was designed to evaluate safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics in children with growth failure due to lysosomal acid lipase deficiency. Its primary efficacy question focuses on survival to a specified age, rather than a comparison between treatment groups. That focus is particularly important when reading the posted results: the endpoint can describe the proportion meeting the survival criterion in this study group, but without a comparator it cannot establish how that proportion differs from what would have occurred under another treatment or without treatment.

The registry record lists additional outcomes, including survival beyond 12 months, growth measures, serum transaminases, ferritin and transfusion-free hemoglobin normalization. Those outcomes broaden the areas assessed, but their presence in the outcome list does not establish what the results were. The clinical question is therefore clear, while the primary numerical answer is not available in the registry record.

3. Trial Design

This was an open-label, single-group study with dose escalation within participants. The registry lists the study as Phase 2 and Phase 3, and reports an enrollment of 9. The study status is completed. Its start date is 2011-05-04 and its primary completion date is 2018-01-03.

Participants received intravenous sebelipase alfa. The study summary describes once-weekly repeat infusions for up to 5 years. The arm description states that participants initially received 0.35 mg/kg once weekly and could escalate to 1 mg/kg once weekly after demonstrating acceptable safety and tolerability during at least 2 infusions. Because treatment was open-label, participants and study personnel were not masked to treatment. There was no randomized allocation or separate control group.

Intra-participant escalation means that a participant's dose could change over time; it does not create independent treatment groups. As a result, the study's observations describe participants receiving the treatment regimen, rather than a randomized contrast between doses. Dose changes and time on treatment may also matter when interpreting outcomes over follow-up, but the registry record does not provide enough detail to characterize those patterns for individual participants.

The primary efficacy analysis set included participants who received any amount of sebelipase alfa and were <=8 months of age on the date of their first infusion. The record states that all 9 participants were included. This population definition is relevant to the primary endpoint and should not automatically be assumed to apply to every secondary outcome or safety summary. The registry record does not report detailed analysis methods for those other outcomes.

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: To assess eligibility, participants were screened for a period of up to 3 weeks prior to enrollment. 11 participants were screened, and 2 participants died during screening. The other 9 participants, all of whom were ≤8 months of age on the date of enrollment, met all eligibility criteria and were enrolled, treated, and analyzed.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The PES included participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa. All 9 participants were included in the PES.

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.

6. Primary Endpoint

The registry lists the primary outcome as Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age, measured over Month 12.

The primary endpoint is the percentage of participants in the primary efficacy analysis set who survived to at least 12 months of age, assessed at Month 12. The analysis set is defined as participants who received any amount of sebelipase alfa and were <=8 months of age at their first infusion. The record states that all 9 enrolled participants were included in this set.

A percentage expresses how many participants in a defined group met a specified outcome. Survival to a stated age is a direct endpoint, and a fixed age threshold makes the outcome interpretable for the population described in the record. It can be useful when the clinical question concerns whether participants reach that milestone. The endpoint does not, by itself, describe the timing of events among participants who did not meet the milestone or explain why an outcome occurred.

The registry identifies a 95% confidence interval as the measure of uncertainty for this endpoint, but the numerical survival estimate and the interval bounds are not reported in the registry record. Without those values, readers cannot assess the observed proportion or how precisely it was estimated. The endpoint definition and analysis population are available; the result needed to answer the primary question is not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study's primary endpoint is a binary outcome for each participant: whether the participant survived to at least 12 months of age. The group-level result is expressed as a percentage. The primary efficacy analysis set is defined in the registry record, and all 9 participants were included. The numerical percentage is not reported, so it is not possible to assess the observed rate from this record.

What does a confidence interval communicate?

General statistical explanation: a confidence interval expresses uncertainty around an estimate under a specified statistical method. It is not a guarantee that the true value lies within the particular interval, and it does not describe the range of individual participant outcomes. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. The registry names a 95% confidence interval for the primary endpoint but does not report the estimate or interval bounds. Therefore, the precision of the primary result cannot be evaluated.

Why does the analysis population matter?

The primary endpoint applies to a defined group, not automatically to every child with the condition. The registry's primary efficacy analysis set includes participants who received any amount of sebelipase alfa and were <=8 months of age at first infusion. All 9 participants met the stated analysis-set definition. That eligibility rule shapes the population to which a result would apply. It does not establish that every participant had complete outcome information or that every secondary analysis used the same population; those details are not reported in the registry record.

What does a single-group design allow?

General statistical explanation: a single-group study can describe outcomes observed among participants receiving a regimen. Without a concurrent comparison group, it cannot directly estimate a treatment contrast. Changes over time may reflect treatment, the natural course of illness, other care or differences in follow-up. Open-label treatment also means masking was not used, which can matter for outcomes involving judgment or reporting. The primary survival endpoint is more objective than a subjective rating, but the design still does not provide a randomized comparison.

How should dose escalation be understood?

The registry describes an intra-participant escalation approach: participants initially received 0.35 mg/kg once weekly and could escalate to 1 mg/kg once weekly after acceptable safety and tolerability during at least 2 infusions. General statistical explanation: when dose changes occur within participants, outcomes at different doses are not equivalent to outcomes from separately randomized dose groups. The participants who reach a higher dose may differ in exposure time and in their experience during earlier treatment. The record does not report dose-specific outcome estimates or methods that account for dose changes.

Why can over-dispersion matter for event counts?

General statistical explanation: over-dispersion occurs when observed variation in counts is greater than a model assumes. It can make standard errors too small if the model does not account for that extra variation. This concept is relevant to some count-data analyses, but the registry record does not report a count model, an over-dispersion assessment or an analysis plan for event counts. It would therefore be inappropriate to assume that a particular model was used.

The record lists a 95% confidence interval for the primary endpoint but does not state the method used to calculate it. It does not report the statistical analysis plan, interim analyses, or methods for handling repeated measurements, missing data, or multiple outcomes. Those omissions limit the ability to reproduce or fully evaluate the analysis from 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("Open-Label Sebelipase Alfa")
n      <- c(9)
events <- c(6)
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  Open-Label Sebelipase Alfa  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and eight secondary outcomes. The secondary outcomes include survival beyond 12 months, median age at death, changes in weight-for-age percentiles and serum measures, counts of participants with growth-related conditions, and transfusion-free hemoglobin normalization. The registry record does not report a multiplicity strategy, such as whether or how the interpretation of several outcome tests was adjusted. Without that information and without numerical secondary results, the chance of misleading findings from examining multiple outcomes cannot be assessed.

The record defines the primary efficacy analysis set: participants who received any amount of sebelipase alfa and were <=8 months of age at first infusion. All 9 participants were included in that set. It does not provide equivalent population definitions for each secondary outcome or the safety summary. The analysis population for those measures is therefore not reported in the registry record.

Methods for missing outcome data are not reported in the registry record. In particular, the record does not explain whether data were incomplete, how missing measurements were handled, or whether any sensitivity analyses were conducted. The absence of a reported missing-data method should not be read as evidence that there were no missing data.

The registry reports no analyses, and numerical results for the listed outcomes are not reported in the registry record. It also does not report an interim-analysis plan or a statistical analysis plan. These gaps prevent a detailed assessment of how outcomes were selected, how uncertainty was handled across measures, and whether the analysis population differed across endpoints.

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: pyrexia (33.3%), catheter site infection (22.2%), device related infection (22.2%), viral infection (22.2%), pallor (11.1%).

The safety summary is for the open-label sebelipase alfa group. It lists 9 participants at risk and 9 affected for serious adverse events, and records 4 deaths. The registry record does not provide the timing or circumstances of the deaths, or establish their relationship to treatment. These figures should be read as observations in this study group, not as evidence that treatment caused an event.

The serious adverse-event terms listed most prominently are pyrexia (33.3%), catheter site infection (22.2%), device related infection (22.2%), viral infection (22.2%), pallor (11.1%) and chills (11.1%). These percentages describe the listed terms in the posted safety summary. The record does not provide term-specific participant counts alongside them, details about event timing, or a comparison group. The percentages therefore do not show how the event frequencies compare with another treatment or with the underlying condition in a similar group.

Because this was a single-group, open-label study with an enrollment of 9, the safety figures describe a small group under the study regimen. They are important for characterizing reported events in the record, but they do not by themselves establish causality or provide a comparative estimate of risk.

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

The registry record documents a study of intravenous sebelipase alfa in children with growth failure due to lysosomal acid lipase deficiency. It describes a single-group, open-label regimen with once-weekly infusions and dose escalation within participants. The primary endpoint was survival to at least 12 months of age among participants in a defined efficacy analysis set.

What the record does not establish is the numerical result for that primary endpoint. The observed percentage and 95% confidence interval are not reported in the registry record. The listed secondary outcomes also lack reported numerical results. Thus, the record does not allow readers to quantify the study's primary outcome, its precision, or the direction and size of any changes in secondary measures.

Even if outcome estimates were available, this design would describe results in the treated study group rather than provide a randomized treatment comparison. There is no separate control group, and allocation is listed as not applicable. Differences between observed outcomes and outcomes in another population could reflect differences in participants, care, follow-up or other factors, rather than treatment alone. The open-label design and intra-participant dose escalation are also relevant when interpreting observations across time and dose.

The safety summary reports serious adverse-event terms, that 9 participants were affected, and 4 deaths. Those figures do not by themselves establish that the treatment caused the events or deaths. The registry does not provide the detail needed to assess timing or make a comparative safety estimate.

The appropriate conclusion is limited to what the registry documents: the study design, defined outcomes and recorded safety summary. It does not report enough numerical efficacy information to determine the observed primary result, and it does not support a causal comparison with another treatment or no treatment.

14. Why This Trial Matters Statistically

This study raises statistical issues that are common in research involving small populations and serious, uncommon conditions. The registry reports an enrollment of 9 and defines the primary endpoint around survival to a specific age. A result from a small study group can be informative as a description of the participants observed, but precision matters: readers need both the estimate and its uncertainty to judge how much information the data contain. The registry identifies a 95% confidence interval but does not report its bounds or the endpoint estimate.

The design also makes the distinction between description and comparison essential. This was a single-group study, not a randomized comparison. Its results, if available, would describe outcomes under the study regimen, but would not independently show how those outcomes differ from a concurrent control group. Dose escalation within participants adds another interpretive layer: exposure could change over time, and results at different doses would not be equivalent to results from separate randomized groups.

Population definitions are equally important. The primary efficacy analysis set has explicit age and treatment-exposure criteria, and all 9 participants were included. That gives readers a clear description of who contributes to the primary endpoint, while leaving the populations for other outcomes unreported. A stated analysis population helps define the scope of an estimate; it does not replace the estimate itself.

Finally, the record illustrates why outcome listings and results must be distinguished. A broad set of survival, growth, laboratory and transfusion-related outcomes is listed, but numerical analyses are not reported. Without those results, multiplicity methods, missing-data handling and analysis details cannot be evaluated. The statistical importance lies both in the design's limits and in the need for complete, interpretable outcome 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 of the registry record is that it does not report the numerical primary efficacy result or its confidence interval. It also lists no analyses, and numerical results for the secondary outcomes are not reported. The endpoint and analysis population are defined, but readers cannot evaluate the observed survival proportion or its precision.

The study had an enrollment of 9 and used a single-group, open-label design. There was no concurrent control group, so the record cannot provide a randomized comparison or separate treatment effects from other explanations for outcomes. Participants underwent intra-participant dose escalation, meaning that exposure could change during follow-up; the registry does not report dose-specific outcome estimates or methods for accounting for those changes.

The primary efficacy analysis set is clearly defined, but the registry does not report analysis populations for each secondary outcome. Missing-data methods, multiplicity methods, interim analyses and a statistical analysis plan are not reported in the registry record. The posted safety summary includes 4 deaths but does not give their timing or circumstances, and it does not establish a relationship to treatment.

The study summary describes weekly treatment for up to 5 years, but the registry record does not report the actual duration of treatment or follow-up for individual participants. These limitations constrain interpretation of both efficacy and safety. They do not indicate what unreported analyses or data might show; they specify what cannot be assessed from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency — NCT01371825.
• Registry record last updated 2019-01-30; status last verified 2019-01.
• Results first posted 2016-04-18.
• 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 record describes a completed, open-label, single-group study of sebelipase alfa in children with growth failure due to lysosomal acid lipase deficiency. It lists Phase 2 and Phase 3, an enrollment of 9, and study dates from 2011-05-04 to primary completion on 2018-01-03.

Participants received intravenous, once-weekly infusions, with dose escalation within participants. The primary endpoint was the percentage of the primary efficacy analysis set surviving to at least 12 months of age. All 9 participants were included in that set. The endpoint estimate and confidence interval are not reported in the registry record. The record lists eight secondary outcomes but reports no analyses.

The safety summary records 9 participants at risk and 9 affected for serious adverse events, and 4 deaths. It lists several serious adverse-event terms with percentages. These observations do not establish causality or provide a comparison with another group.