An Efficacy and Safety Study of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Efficacy and Safety Study of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia (NCT03510715), a na phase 3 study. The primary outcome is Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis.

2. Clinical Question

The clinical question is about change in a laboratory measure during treatment, rather than a comparison of alirocumab against a randomized alternative. Participants had homozygous familial hypercholesterolemia and were already receiving background treatments. The registry lists several lipid-lowering drugs among the interventions, but does not describe a control group allocated to those treatments alone.

The main outcome was LDL-C percent change at Week 12. Secondary objectives concerned LDL-C at later time points, other lipid measures, and safety and tolerability through 48 weeks. These objectives describe what the study sought to evaluate; they do not establish what the results were. The registry record does not report a numerical primary estimate, its standard error, or a confidence interval, so the magnitude and precision of the Week 12 change cannot be assessed from the recorded result.

3. Trial Design

This was a Phase 3, completed, open-label, single-group study. The registry reports enrollment of 18 participants and lists the condition as hypercholesterolemia. The study started on 2018-08-31, had primary completion on 2020-02-17, and is recorded as completed. No randomized allocation or masking is reported; allocation is listed as not applicable and masking as none.

Participants were children and adolescents aged 8 to 17 years with homozygous familial hypercholesterolemia. The study evaluated alirocumab on top of background treatment. Its primary objective was to evaluate LDL-C at Week 12. Secondary objectives covered LDL-C after 24 and 48 weeks, other lipid parameters at the specified follow-up times, and safety and tolerability through 48 weeks.

The registry describes weight-dependent alirocumab dosing, with 75 or 150 mg administered every 2 weeks. It also identifies statins and ezetimibe among the listed interventions. The available arm description is incomplete, so the full dosing and treatment rules are not reported in the registry record. The primary analysis was planned for the combined dose population rather than a separate efficacy assessment of each dose.

Because this was a single-group study without random assignment, the design estimates outcomes observed during treatment, not a treatment effect relative to a concurrent randomized control. Changes from baseline can be described, but they cannot by themselves distinguish treatment-related change from other explanations such as the course of the condition, background treatment, or changes over time. The open-label design also means treatment assignment was not masked. The registry record does not describe additional design features such as an interim analysis plan or a formal sample-size justification.

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: A total of 18 participants were enrolled and received treatment in this study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on ITT population which included all enrolled participants who had received at least one dose or partial dose of alirocumab. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e. for combined population).

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: Analysis was performed on all enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis, measured over Baseline to Week 12.

The primary endpoint was percent change from baseline in low-density lipoprotein cholesterol at Week 12. LDL-C is a blood lipid measure; expressing the outcome as percent change describes change relative to each participant’s baseline value rather than reporting only an absolute concentration. The registry specifies an adjusted least-squares mean as the summary measure and a standard error as its dispersion measure.

Using a continuous lipid measure allows the analysis to summarize the average change across participants while retaining differences in the size and direction of individual changes. A mean can be informative about the overall pattern, but it does not show how widely individual responses varied. The standard error describes uncertainty in the estimated mean; it is not the spread of individual participant outcomes. A confidence interval would give a range of values compatible with the data under the analysis assumptions, but no confidence interval for the primary result is reported in the registry record.

The endpoint was defined over baseline to Week 12, while the stated model used available post-baseline observations from Week 4 through Week 48. The registry says this repeated-measures model was used to account for missing data and included observations regardless of on- or off-treatment status. The numerical Week 12 estimate itself is not reported in the registry record. Consequently, the endpoint definition and method can be described, but the amount and precision of the observed change cannot be assessed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure, summarized as a least-squares mean percent change from baseline in LDL-C at Week 12. A least-squares mean is a model-based estimate of an average outcome. It can account for the structure of the fitted analysis, rather than being only the arithmetic average of values observed at a single visit. The registry describes the estimate as adjusted, but does not report the numerical estimate or further details about the adjustments.

What does the standard error describe?

The reported type of dispersion for the primary measure is the standard error. In general, a standard error describes how uncertain an estimated mean is because it is based on a sample rather than the entire population of interest. It does not describe the range or variability of individual participants’ measurements. A confidence interval is often used to communicate uncertainty around an estimate by giving a range of values compatible with the data and analysis assumptions. No primary standard error or confidence interval is reported in the registry record, so neither the size nor the precision of the estimated change can be assessed.

What is a repeated-measures model?

In general, a mixed model for repeated measures uses observations collected from the same participants at multiple visits while accounting for the fact that observations from one participant are related. The registry says the model used available post-baseline observations from Week 4 through Week 48 and was intended to account for missing data. It also states that observations were included regardless of whether participants were on or off treatment. This means the planned model drew on longitudinal information, rather than restricting its input to the Week 12 visit alone.

Using repeated observations can make use of data from participants who have measurements at some visits but not others. However, the model does not make missing outcomes known. Its results depend on the data available and on assumptions about how missingness relates to observed and unobserved outcomes. The registry record does not report the missing-data patterns, the number of observations contributing at each visit, or sensitivity analyses testing alternative assumptions. It also does not report enough model detail to describe every specification choice.

What does the analysis population include?

The primary analysis population is described as all enrolled participants who received at least one dose or partial dose of alirocumab. The registry calls this the ITT population. In general, intention-to-treat principles aim to preserve the groups formed by random assignment, whether or not participants follow treatment as planned. Here, however, the study is single-group and has no randomized allocation. The stated population definition should therefore be read as the registry’s operational definition for the efficacy analysis, not as evidence of a randomized comparison.

The record says the efficacy analysis was planned for all doses combined. The dosing description refers to 75 or 150 mg every 2 weeks depending on body weight. An overall combined analysis summarizes the study population as a whole under that dosing approach; it does not isolate a dose-specific effect. The arm description is incomplete, and the registry does not report separate dose-specific primary estimates.

Why does study design matter for interpretation?

In general, randomization supports comparisons by making treatment groups more comparable on average with respect to both measured and unmeasured characteristics. This study did not use randomized allocation and had no control group. A change from baseline can be described, but without a concurrent comparator it cannot establish what would have happened to the same participants over the same period without alirocumab. The open-label design also means the treatment was not masked, although the endpoint is a laboratory measure.

Statistical methods can help summarize observed data and quantify uncertainty, but they cannot replace a missing comparator or a missing result. The registry describes the primary method but does not report the primary numerical estimate, standard error, confidence interval, or analysis entries. Thus, the statistical approach is identifiable at a broad level, while the result and important details needed to evaluate its precision are unavailable in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Alirocumab")
n   <- c(18)
m   <- c(-4.1)
sp  <- c(9)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Alirocumab  18  -4.100  38.184  -23.088  14.888

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary LDL-C outcome and multiple secondary lipid outcomes, including additional LDL-C time points and measures such as apolipoprotein B, non-HDL-C, total cholesterol, lipoprotein a, HDL-C, and triglycerides. It reports 13 outcome measures. Evaluating many outcomes and time points can create a multiplicity problem: in general, the more statistical questions considered, the greater the chance that some findings appear notable by chance if each is interpreted without adjustment.

The registry record does not report a multiplicity adjustment strategy, a hierarchy for testing secondary outcomes, or a detailed statistical analysis plan. It also does not report analysis entries. Therefore, the intended handling of multiple comparisons and the inferential status of secondary results are not reported in the registry record. The secondary objectives identify measures of interest but do not establish that every outcome was tested or that any result was statistically significant.

For missing data, the primary outcome description states that a mixed model for repeated measures used all available post-baseline observations from Week 4 through Week 48 and was intended to account for missing data. The registry does not report how much data were missing, why observations were missing, or whether sensitivity analyses were conducted. In general, a model can use incomplete longitudinal records under assumptions about the missingness process, but it cannot guarantee that those assumptions hold. The impact of missing data on the estimate is therefore not assessable from the registry record.

The analysis population included enrolled participants who received at least one dose or partial dose, and efficacy analysis was planned for all doses combined. How exclusions, treatment discontinuation, or other protocol deviations were handled is not reported in the registry record.

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: cardiac failure (11.1%).

The registry reports serious adverse event figures under two alirocumab group labels. For “Alirocumab 75 mg Q2W/up to 150 mg Q2W,” 9 participants were at risk and 1 was reported as affected by a serious adverse event. For “Alirocumab 150 mg Q2W,” 9 participants were at risk and 0 were reported as affected. The record also reports 1 death in the first group and 0 in the second. These are descriptive counts, not estimates from a randomized comparison.

The relationship between the two group labels and whether they represent distinct participants is not clarified in the registry record. The figures should not be added together or treated as independent groups without that information. The record lists Cardiac Failure as a serious adverse event term at 11.1%, but does not establish a causal relationship between that event and alirocumab.

Other adverse events are reported as affecting 8 of 9 participants in the first group and 9 of 9 in the second. These counts indicate how many participants were reported as affected, not how many total event episodes occurred. The registry record does not provide enough context in these figures to judge severity, timing, relatedness, or comparison with untreated risk. A single-group, open-label study cannot determine from these counts alone whether an event was caused by treatment.

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

The study was designed to evaluate alirocumab in children and adolescents with homozygous familial hypercholesterolemia who were receiving background treatment. It defined a primary laboratory outcome, percent change from baseline in LDL-C at Week 12, and described a model intended to use repeated measurements and available data. Those details clarify the question and the planned analysis, but they do not disclose the observed primary result.

The numerical primary estimate, its standard error, and its confidence interval are not reported in the registry record. As a result, readers cannot determine from this record the direction or size of the average Week 12 change, or how precisely it was estimated. The enrollment of 18 participants describes the study’s size; it does not convey the strength, direction, or certainty of an outcome.

Even if a baseline-to-follow-up change were available, the single-group design would limit causal interpretation. There was no randomized control group to show how LDL-C would have changed over the same period under a different treatment or without alirocumab. Background treatments and other changes over time remain part of the context. The open-label design and combined-dose efficacy analysis also mean the registry does not provide a blinded comparison or a randomized estimate separating the dose groups.

The safety counts describe events recorded in the registry, but do not establish whether alirocumab caused them. The relationship between the listed group categories is not clarified, and there is no randomized comparator against which to interpret event rates. Secondary outcomes and safety objectives identify additional questions the study intended to assess; absent numerical results, they cannot support conclusions about the size or consistency of observed changes.

Accordingly, the record can be read as a description of the study question, design, outcome definitions, and analysis approach. It does not support a conclusion about the magnitude or precision of the primary efficacy result, nor a causal conclusion about safety. Those limitations arise from the unavailable result details and the single-group design, not from the statistical terminology alone.

14. Why This Trial Matters Statistically

This study is statistically notable for the population and design it addresses: children and adolescents with homozygous familial hypercholesterolemia, enrolled in a Phase 3, open-label, single-group study. The primary question focuses on a continuous biomarker and change from baseline. Such a setup makes the distinction between describing change and estimating a comparative treatment effect especially important.

The registry specifies a model-based least-squares mean and a standard error, and describes a repeated-measures model using available observations over follow-up. These choices indicate an effort to summarize an average outcome while using longitudinal data. They also illustrate why statistical reporting needs to include the estimate and its uncertainty, as well as enough information to understand missing observations and model assumptions. Those numerical result details are not reported in the registry record.

Combining doses for the planned efficacy analysis is another relevant feature. It provides an overall description under the weight-dependent dosing approach, but it does not answer a randomized dose-comparison question. Since allocation was not randomized and no comparator arm is described, any observed change would remain a within-group finding rather than a controlled estimate of effect.

The registry also lists several secondary lipid outcomes and safety objectives. Considering multiple outcomes requires clarity about which analyses are confirmatory and how multiplicity is handled. That strategy is not reported in the registry record. This trial therefore highlights both the value of clearly defining a primary endpoint and the limits of interpretation when numerical results, uncertainty, and analysis details are unavailable.

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 main limitation for interpreting efficacy is that the registry record does not report the numerical primary outcome, its standard error, or a confidence interval. It also does not provide numerical results for the listed secondary lipid outcomes. The analysis method can be described, but its estimate and precision cannot be evaluated.

The trial had a single group and no randomized control arm. Baseline-to-follow-up change therefore cannot be separated from other influences over time, including background treatment. The open-label design and combined-dose efficacy analysis further limit what can be learned about blinded effects or differences between doses.

The registry reports enrollment of 18 participants. It does not report the rationale for that enrollment, a formal sample-size justification, or an interim analysis plan. The record also does not provide the missing-data pattern, visit-specific numbers analyzed, reasons for missing observations, or sensitivity analyses. These omissions make it difficult to assess how incomplete follow-up may have affected the model-based estimate.

The arm description is incomplete, and the registry does not clarify the relationship between the two adverse-event group labels. Consequently, their figures should not be interpreted as independent or directly comparative groups. The safety record also does not establish causality for the listed events. Finally, the approach to multiplicity and the detailed statistical analysis plan are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Efficacy and Safety Study of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia — NCT03510715.
• Registry record last updated 2020-12-29; status last verified 2020-10.
• Results first posted 2020-12-29.
• 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

NCT03510715 is a completed Phase 3, open-label, single-group study of alirocumab in children and adolescents aged 8 to 17 years with homozygous familial hypercholesterolemia. Enrollment was 18. The study evaluated alirocumab every 2 weeks on top of background treatment, with dosing described as dependent on body weight.

The primary outcome was percent change from baseline in LDL-C at Week 12, summarized using an adjusted least-squares mean from a repeated-measures model. Efficacy analysis was planned for participants who received at least one dose or partial dose, with doses combined. Secondary objectives included other lipid outcomes and safety through 48 weeks.

The numerical primary result and its uncertainty are not reported in the registry record. The absence of a randomized comparator means the design does not provide a controlled treatment-effect estimate. Safety figures are descriptive, and the record does not establish event causality.