A Study of ALN-PCSSC in Participants With Homozygous Familial Hypercholesterolemia (HoFH): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of ALN-PCSSC in Participants With Homozygous Familial Hypercholesterolemia (HoFH) (NCT02963311), a na phase 2 study. The primary outcome is Percentage Change From Day 1 to Day 90 in LDL-C.

2. Clinical Question

The study’s stated purpose was to assess the safety, tolerability, and efficacy of ALN-PCSSC in people with HoFH. Its primary outcome focuses on LDL-C, a blood measure relevant to the condition, and compares its value at the start of the study with its value at the later assessment. This is a within-participant change question, not a comparison of outcomes between randomized treatment groups.

The registry record does not report a numerical estimate for the primary outcome. It therefore does not establish the size or precision of the observed LDL-C change. The record also describes the endpoint results as descriptive because of the small number of participants and non-normal data, with no inferential analysis and limited summary statistics. Any interpretation must remain within those limits.

3. Trial Design

This was a Phase 2, open-label, single-group, multicenter pilot study of ALN-PCSSC in participants with homozygous familial hypercholesterolemia. The record lists enrollment of 9 and a completed status. The recorded study start was 2016-12-13, and the primary completion date was 2018-10-08. Allocation is listed as not applicable, and masking is listed as none.

The intervention description specifies ALN-PCSSC at 300 milligrams, administered subcutaneously on Day 1. It also describes a conditional second dose: participants whose mean serum PCSK9 levels were not suppressed by >70% compared with baseline at Day 60 or Day 90 were to receive a further dose at Day 90 or Day 104, respectively, based on PCSK9. The record lists Standard of Care as an intervention but does not describe a separate concurrent control arm. Its stated single-group design means the posted results are not a randomized treatment comparison.

The primary endpoint was percentage change in LDL-C from Day 1 to Day 90. Secondary outcomes include absolute LDL-C change, PCSK9 changes at Day 60 and Day 90, and changes in total cholesterol, triglycerides, and HDL-C at specified follow-up visits. The record lists 21 outcome measures and 0 analyses. It does not report details of the protocol, analysis populations, or a statistical analysis plan, so those features cannot be reconstructed from the registry entry.

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:

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 Change From Day 1 to Day 90 in LDL-C, measured over Day 1, Day 90.

The primary endpoint is percentage change in LDL-C from Day 1 to Day 90. It expresses the follow-up LDL-C value as a relative change from the Day 1 value. In general, a percentage-change measure can help describe change on a common relative scale when starting values differ, while an absolute-change measure describes the difference in the original measurement units. The record also lists absolute LDL-C change as a secondary outcome.

LDL-C is a blood lipid measure relevant to HoFH, so tracking it provides a biochemical measure of change during the study. That explains what the measure captures, but the registry record does not report why this endpoint was selected over other possible measures or how the assessment timing was justified. The primary outcome is a within-group measure over follow-up, not a direct estimate of how outcomes compare with an untreated or standard-care control group.

The endpoint is specified as a mean, with a 95% confidence interval as its dispersion measure. However, the numeric estimate and confidence interval are not reported in the registry record. The endpoint description says results are presented as descriptive statistics because the number of subjects was small and the data were not normally distributed, with no inferential and limited summary statistics. Thus, the endpoint definition is available, but its observed magnitude and precision cannot be assessed from the reported entry.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary outcome as a mean percentage change in LDL-C from Day 1 to Day 90, with a 95% confidence interval. It also says that data were presented descriptively because the number of subjects was small and the data were not normally distributed, with no inferential analysis and limited summary statistics. The numeric endpoint results themselves are not reported in the registry record. The concepts below explain how such summaries are generally read; they do not add analyses to this trial.

What does a mean summarize?

In general, the mean is calculated by combining measured values and dividing by the number of observations. It provides a central summary, but it can be influenced by unusually high or low values. When data are not normally distributed, the mean may not describe the typical participant especially well. A distribution may be uneven or contain extreme observations, so a mean is best understood alongside information about the spread and shape of the data. The record says that limited summary statistics were presented, but it does not report the underlying participant-level values or enough detail to assess the distribution directly.

What does a confidence interval communicate?

In general, a confidence interval gives a range of values compatible with an estimate under the assumptions of the method used. Its width conveys precision: a narrower interval indicates greater precision than a wider interval, all else being equal. The interval does not show the range of individual participant outcomes, and it does not correct for bias or limitations in study design. A 95% confidence interval is the dispersion measure named for this endpoint, but its numeric bounds are not reported in the registry record. Therefore, its width and the precision of the estimated mean cannot be assessed.

Why does non-normality matter?

In general, methods based on normal-distribution assumptions can behave poorly when the data depart substantially from those assumptions, particularly when there are few observations. Skewness or extreme values may affect estimates and uncertainty calculations. Alternative summaries or methods may sometimes be appropriate, but the registry record does not specify that an alternative inferential method was used. Instead, it explicitly describes the results as descriptive and says there was no inferential analysis. The specific checks, transformations, or alternative methods considered are not reported in the registry record.

What can a descriptive before-and-after comparison establish?

In general, a change from baseline describes what happened over time among the people observed. It does not alone establish what would have happened over the same period without the intervention. A concurrent control group can help distinguish treatment contrasts from time-related changes, but this study is described as single-group and open-label, with allocation listed as not applicable. The record does not describe a like-for-like control comparison. Thus, the design supports a descriptive account of observed change if results are reported, but not a randomized estimate of comparative treatment effect.

How should planning calculations be read?

In general, sample-size calculations describe the number of participants that a hypothetical design would need under stated assumptions. They are planning illustrations, not results from enrolled participants and not evidence that a study had a particular probability of detecting an effect. The registry’s planning assumptions describe a two-arm illustration with equal allocation, a two-sided significance level of 0.05, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Those assumptions do not describe the actual single-group trial design. The scenario-specific participant counts and the observed effect used for planning are not reported in the registry record, so no planning estimate can be interpreted as observed power for this study.

More broadly, a statistical summary is only as informative as its data and methods. The record does not provide the numerical primary endpoint estimate, the confidence interval, the participant-level distribution, or inferential analyses. This prevents independent assessment of the estimated change, its uncertainty, and the sensitivity of the summary to the non-normal data. The stated descriptive approach is clear, but the amount of detail available is limited.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures. These include a primary LDL-C endpoint and secondary measures involving LDL-C, PCSK9, total cholesterol, triglycerides, and HDL-C at specified follow-up times. Examining multiple outcomes or time points creates a general multiplicity concern: when many questions are considered, the chance of at least one apparently notable result can increase if each is assessed separately. This does not mean any result in this study is false; it means the interpretation depends on which outcomes were planned and how results were selected or adjusted.

The registry record does not report a multiplicity strategy, such as a hierarchy of confirmatory outcomes or an adjustment method. It also lists 0 analyses and does not provide numerical outcome results. It is therefore not possible to determine how multiplicity was handled in the analysis or to distinguish prespecified findings from exploratory ones.

Missing-data methods and analysis populations are not reported in the registry record. The entry does not specify how missing follow-up measurements were handled, whether participants with incomplete visits were included in each outcome summary, or what rules defined the analysis population. These omissions matter because the available measurements may differ from the measurements that would have been observed had all follow-up data been complete. Without the participant flow and missing-data approach, the extent and potential influence of incomplete data cannot be assessed.

Details about interim analyses, protocol deviations, and the planned statistical analysis strategy are also not reported in the registry record. No particular approach should be assumed. These gaps limit evaluation of how faithfully the posted summaries reflect the original analysis plan.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: angina unstable (25.0%).

The safety summary labels the group “Inclisiran.” It reports 4 participants at risk for serious adverse events, with 1 affected; for other adverse events it reports 4 at risk and 3 affected. Deaths are reported as 0. “Angina unstable” appears among the top serious terms with a listed value of 25.0%. These are descriptive entries in the registry record; they are not a controlled comparison of safety between treatment groups.

The at-risk and affected figures should be read as reported, without treating them as proof that the intervention caused an event. The record does not provide the event narratives, timing, duration, recurrence, severity beyond the serious-event classification, or relationship assessments needed for a fuller clinical interpretation. The listed percentage for “Angina unstable” is not accompanied in the record by enough context to reconstruct its basis, so it should not be converted into a count or interpreted as a comparative risk.

Because the study is single-group and open-label, the safety summaries do not establish how these events compare with what would have been observed under another treatment or under standard care alone. They describe reported events within the study, rather than estimating a causal difference in risk.

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

The registry record identifies a pilot study of ALN-PCSSC in people with HoFH and specifies percentage change in LDL-C from Day 1 to Day 90 as its primary endpoint. It also describes the study as completed and reports enrollment of 9 participants. These details establish the study’s purpose, design, and planned measurement, but they do not reveal the observed primary outcome: its numerical estimate and confidence interval are not reported in the registry record.

As a result, the posted information does not show the size, direction, or precision of the primary LDL-C change. It cannot support a claim that the intervention did or did not alter LDL-C. The same restriction applies to the listed secondary outcomes, for which numerical results are not reported in the registry entry. The specified endpoint and follow-up schedule are not substitutes for outcome estimates.

In general, a single-group before-and-after study can describe changes among participants, but those changes cannot be compared with a concurrent control group in this design. Any change could also be affected by factors unrelated to the study intervention. This means the design does not provide a randomized estimate of comparative effect. The limitation applies regardless of whether a change was favorable, unfavorable, or absent.

The safety counts offer a descriptive record of reported events, including serious adverse events and deaths, but they do not establish causation or comparative safety. The registry does not give the clinical detail needed to assess individual event histories. In addition, missing-data handling, analysis populations, and multiplicity procedures are not reported.

Overall, the record is informative about the study question and design, but its available statistical reporting is insufficient to judge the primary result or the precision of an effect estimate. Interpretation should distinguish the existence of a planned endpoint from evidence about its observed value.

13. Why This Trial Matters Statistically

This study raises important statistical issues because it combines a small pilot design, a single-group structure, and an outcome description that explicitly notes non-normal data. Each feature affects what can be learned from the results. A pilot can provide descriptive information in the population studied, but a small body of observations may yield imprecise estimates and provide limited ability to characterize variability. The registry itself cites the small number of subjects as a reason for presenting descriptive statistics.

The single-group design also shapes the interpretation. A change between baseline and follow-up is not the same as a treatment contrast against a concurrent control. Statistical summaries cannot remove this design limitation; the record does not establish what would have happened over the same period without ALN-PCSSC. This makes it especially important to avoid treating a within-group change, if reported, as a randomized causal estimate.

Non-normality matters because common summaries and uncertainty methods can be sensitive to the distribution of the data. The registry’s stated choice to use descriptive reporting, with no inferential analysis, is therefore central to understanding the evidence. At the same time, the absence of the numerical estimate and confidence interval prevents readers from evaluating the actual magnitude and precision of the primary endpoint.

The record also lists 21 outcome measures, raising the general need to understand outcome selection and multiplicity. The analysis plan and multiplicity approach are not reported. Together, these points make clear why statistical interpretation depends not just on an endpoint label, but on the design, data distribution, analysis details, and completeness of the posted results.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The key limitation for interpretation is that the registry record does not report the numerical primary endpoint result or its 95% confidence interval. The outcome is defined, but readers cannot assess the estimated percentage change in LDL-C or its precision. Numerical results for the listed secondary outcomes are also not reported in the registry entry.

The study is described as open-label and single-group, with allocation listed as not applicable and masking listed as none. No concurrent control comparison is specified. This prevents a direct randomized comparison and limits causal interpretation of any before-and-after change. The record lists Standard of Care in its intervention information but does not describe it as a separate control arm in the single-group design.

The registry describes the data as non-normal and the number of subjects as small, and says that results are descriptive, with no inferential analysis and limited summary statistics. Participant-level distributions and further details about the descriptive summaries are not reported. Therefore, the robustness of any mean to skewness or extreme observations cannot be assessed from this record.

Analysis populations, missing-data handling, multiplicity procedures, interim analyses, and a detailed statistical plan are not reported in the registry record. The record also does not provide enough safety-event detail to assess event timing, course, or relatedness. These limitations do not demonstrate that a particular bias or problem occurred; they identify information needed for a fuller appraisal that is not available in the registry entry.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of ALN-PCSSC in Participants With Homozygous Familial Hypercholesterolemia (HoFH) — NCT02963311.
• Registry record last updated 2020-05-18; status last verified 2020-05.
• Results first posted 2020-05-18.
• 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.

18. Record Summary

NCT02963311 is a completed Phase 2, open-label, single-group, multicenter pilot study of ALN-PCSSC in participants with homozygous familial hypercholesterolemia. Enrollment was 9. The recorded study start was 2016-12-13, and primary completion was 2018-10-08. The primary endpoint was percentage change in LDL-C from Day 1 to Day 90.

The registry describes outcome reporting as descriptive because the number of subjects was small and the data were not normally distributed. It states that no inferential analysis and limited summary statistics were presented. The numerical primary endpoint estimate and confidence interval are not reported in the registry record. The entry lists 21 outcome measures and 0 analyses; details about missing data, analysis populations, and multiplicity are not reported.

The adverse-event summary reports serious events, other adverse events, and deaths for a group labeled Inclisiran, including “Angina unstable” as a top serious term. These entries are descriptive and do not provide a controlled comparison.