A Study of Inclisiran 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 Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH) (NCT03851705), a randomized phase 3 study. The primary outcome is Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150.

2. Clinical Question

The question is about the between-group difference in a measured lipid outcome at a specified follow-up visit. It is not, by itself, a direct comparison of clinical events or long-term outcomes. The registry also lists safety, tolerability, and efficacy as study aims, and lists secondary measures of LDL-C and PCSK9 over later visits.

The study had a two-part design: the first part was double-blind and placebo-controlled, while the second part was open-label. The primary comparison concerns Part 1. The later part included inclisiran dosing for participants, but the complete transition and dosing details are not reported in the registry record.

3. Trial Design

This was a Phase III, randomized, double-blind, parallel-group study with a two-part design. Part 1 compared inclisiran with placebo under double-blind conditions. The registry reports 37 participants in the Part 1 inclisiran arm and 19 in the Part 1 placebo arm for the primary endpoint. It does not report the randomization procedure or allocation ratio.

In Part 1, inclisiran was given as 300 mg by subcutaneous injection on Day 1 and Day 90. The placebo arm received placebo injections on those days. The second part was open-label and included inclisiran dosing on Day 270, Day 450, and Day 630 for participants assigned to that part. The description of dosing for participants initially assigned to placebo is incomplete in the registry record, so the full sequence cannot be characterized from the record.

The primary endpoint was percent change in LDL-C from baseline to Day 150. The primary population is described as the intent-to-treat population, consisting of all participants randomized into the study. The registry lists an enrollment of 56. The study status is completed; the recorded study start was 2019-02-06 and primary completion was 2020-03-02.

The registry does not report the planned sample-size justification, the randomization method, or a detailed statistical analysis plan. The record also does not establish whether the primary comparison was the only confirmatory analysis. These details matter when judging the strength and intended role of a reported comparison, rather than only its numerical result.

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.

Part 1: Double-Blind Period

Reasons for not completing this period:

Part 2: Open-Label Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT Population: All participants randomized into the study comprised the intent-to-treat (ITT) 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.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150, measured over Baseline, Day 150.

The primary endpoint is percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 150. It expresses the change in LDL-C relative to each participant’s baseline value, then summarizes that measure for the study groups. LDL-C is a continuous measure, so the analysis can describe both the direction and magnitude of average change rather than reducing the endpoint to a yes-or-no event.

The registry reports least-squares mean estimates for each Part 1 arm. The placebo-arm estimate was 2.39, with a 95% confidence interval from -19.98 to 24.75. The inclisiran-arm estimate was 0.7, with a 95% confidence interval from -14.03 to 15.44. These are group-level estimates; they do not describe the range of individual participant responses.

A fixed assessment visit makes the comparison interpretable at a defined point in follow-up. The endpoint is useful for quantifying a change in a laboratory measure, but it does not directly measure clinical events. Its interpretation also depends on how baseline values, missing observations, and the planned statistical comparison were handled. The relevant details of missing-data handling are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a percentage change in LDL-C. For a continuous outcome, a group mean summarizes the average value, while an interval communicates uncertainty around that estimate. The registry describes the group estimates as least-squares means and gives 95% confidence intervals. A least-squares mean is a model-based mean; unlike a simple arithmetic average, it can reflect the covariates included in the fitted model. The registry does not specify the covariates used for the arm estimates.

A confidence interval is a range of values compatible with the data and the model under the method used. A wider interval indicates less precision than a narrower one. It should not be read as a range containing most individual participants’ values. For the primary comparison, the reported 95% confidence interval runs from -29.19 to 25.83 around the mean difference of -1.68. Because the interval includes no difference and extends in either direction, the estimated difference is not precise enough to settle its direction or magnitude.

The sponsor’s reported primary comparison uses ANCOVA. In general, analysis of covariance models an outcome while accounting for selected covariates; this can improve precision when the covariates are relevant and appropriately specified. The registry labels the parameter as a mean difference in final values, but does not report the model covariates, assumptions, or diagnostic checks. The reported estimate and interval should therefore be interpreted as the result of the registry-listed model, not as a fully reproducible analysis description.

Randomization supports a comparison between assigned groups by reducing systematic differences at allocation, on average. Double masking in Part 1 is intended to limit knowledge of assignment from influencing behavior or outcome assessment. The registry identifies the study as randomized and double-blind, but does not report operational details such as who was masked or how allocation concealment was implemented. The parallel-group structure means the Part 1 comparison is between groups followed concurrently, rather than a within-participant crossover comparison.

Statistical significance and clinical importance are different questions. A p-value evaluates how compatible the data are with a specified null model, given the analysis assumptions; it does not give the probability that the null hypothesis is true, nor does it measure the size or importance of an effect. The reported p-value is 0.905. The confidence interval is more informative about the range of effect sizes compatible with the model, and it remains broad. The registry does not report a prespecified clinically important difference for this endpoint, so the clinical importance of particular values within the interval cannot be judged from the record.

The secondary binary endpoint uses a threshold for LDL-C reduction. For a binary outcome, the number meeting the criterion and the number assessed define the observed group proportions; a risk difference expresses the difference between those proportions. The posted recalculation for this outcome is unadjusted. Its planning illustrations use the observed effect as a planning input and vary the assumed fraction of that effect, with two-sided significance level 0.05, equal allocation, and a normal approximation. Those figures are planning illustrations, not observed power and not the trial’s own sample-size justification. The registry does not report the original design assumptions behind enrollment.

Multiplicity arises when many outcomes, visits, or analyses are examined. Even when each individual test uses a conventional threshold, the chance of at least one apparently positive result can increase across a collection of tests. The record lists 52 outcome measures, 51 secondary outcomes posted, and 60 analyses. No adjustment for multiplicity or hierarchy among secondary outcomes is reported in the registry record. Thus, secondary findings should be treated as exploratory unless a prespecified testing strategy is documented elsewhere in the record.

Over-dispersion is a general concern for count or binary data when observed variability exceeds what a simple model assumes. In that situation, standard errors can be too small and intervals too narrow if the model does not accommodate the extra variability. The primary endpoint is continuous, and the registry lists ANCOVA for its comparison; it does not report a dispersion assessment. This general issue does not establish that over-dispersion affected this analysis.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparison as an ANCOVA estimate of the mean difference in final values: -1.68, with a 95% confidence interval from -29.19 to 25.83. The reported p-value is 0.905. The interval includes no difference and is broad, so the sponsor’s analysis does not yield a precise estimate of the between-group effect at Day 150.

The registry’s arm-level least-squares means are 2.39 for placebo and 0.7 for inclisiran. Those values are group estimates, while the ANCOVA result is the sponsor-reported comparison between groups. They should not be treated as interchangeable summaries: the comparison is the direct statistical result addressing the primary question.

The registry record does not flag a discrepancy between the sponsor analysis and a recalculation. The sponsor’s own analysis therefore remains the primary basis for describing the primary result. Any simple unadjusted recalculation from summary statistics would not reproduce the covariate-adjusted ANCOVA model, particularly because the model covariates and other implementation details are not reported. The registry record does not provide enough information to independently reconstruct that model.

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies the intent-to-treat population as all participants randomized into the study. That definition indicates the intended population for the primary analysis, but the record does not describe how the analysis handled participants without a Day 150 measurement, deviations from assigned treatment, or other missing outcome data. The missing-data method and any sensitivity analyses are not reported in the registry record.

For the primary endpoint, the arm estimates are reported for 37 participants in the inclisiran group and 19 in the placebo group. For the secondary threshold endpoint, the posted denominators are 34 and 18, respectively. The registry does not explain the difference between these endpoint denominators and the primary endpoint group counts. It would be inappropriate to infer why observations were unavailable or how that affected the estimates.

The study record includes 52 outcome measures, 51 secondary outcomes posted, and 60 analyses. Multiple endpoints, time points, and comparisons raise a multiplicity concern: without a prespecified hierarchy or adjustment, the chance of at least one apparently unusual result can rise as more analyses are examined. Whether the trial used a formal testing sequence, multiplicity adjustment, or another control strategy is not reported in the registry record.

The registry does not report the detailed statistical analysis plan, interim analyses, or the sample-size justification. Consequently, the intended status of the secondary analyses and the handling of missing data cannot be established from the record. The primary result can be described as posted, but the extent to which the reported analyses followed a prespecified plan is not clear.

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: family stress (5.3%), aortic valve stenosis (3.8%), pneumonia viral (3.8%), non-cardiac chest pain (2.7%), endocarditis (2.7%).

In Part 1, serious adverse events were reported for 2 participants in the inclisiran group, with 37 at risk, and for 1 participant in the placebo group, with 19 at risk. For Part 2, the registry reports 11 participants with serious adverse events among 53 at risk. It also reports 3 deaths in Part 2. No deaths were reported for the Part 1 groups.

These are counts within the registry’s stated at-risk groups. They do not establish that an event was caused by treatment. The Part 2 figure is from an open-label period and is not a concurrent randomized comparison with the Part 1 placebo group, so direct comparison across those parts would be difficult to interpret.

The registry lists several serious adverse-event terms, including family stress, aortic valve stenosis, viral pneumonia, non-cardiac chest pain, endocarditis, and adenocarcinoma of colon. The listed percentages describe reported terms, not necessarily treatment-related events. The record does not provide enough detail to assess timing, relatedness, severity beyond the serious-event classification, or comparative risk over equivalent exposure.

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

The primary result is an estimate of the difference between randomized groups in percent change in LDL-C at Day 150. The sponsor-reported ANCOVA estimate is -1.68, and its 95% confidence interval ranges from -29.19 to 25.83. This is an imprecise estimate: the interval includes no difference and also allows effects in either direction. The reported comparison does not establish a clear between-group difference, but it also does not demonstrate that the groups are equivalent.

The confidence interval communicates uncertainty in the estimated group comparison under the model. It does not predict the result for an individual participant, and it does not by itself determine whether values within the interval would be clinically important. The registry does not report a threshold for clinical importance, so that judgment cannot be made from the statistical result alone.

The endpoint is a laboratory measure at a particular visit, not a direct measure of clinical events. The result therefore does not answer whether participants experienced changes in health outcomes beyond the measured LDL-C endpoint. It also does not resolve the effects of treatment over the full open-label period, where the design and comparison differ from Part 1.

Interpretation is further limited by missing details about analysis covariates, missing-data handling, multiplicity, and the study’s planned sample-size justification. The result should be understood as the registry-reported estimate for the specified primary endpoint and analysis, with the uncertainty and design limitations—not as a universal or definitive conclusion about treatment effects.

14. Why This Trial Matters Statistically

This trial illustrates why the estimated between-group effect and its confidence interval deserve more attention than an isolated significance label. The registry reports a point estimate and an interval that spans no difference and a broad range of possible effects. That combination conveys uncertainty directly: the analysis does not pin down a precise direction or magnitude.

It also shows the importance of distinguishing an arm-level estimate from the comparative analysis. The least-squares mean for each group describes the modeled group outcome, while the ANCOVA mean difference addresses the randomized comparison. The latter is the statistic that most directly corresponds to the primary question, although the registry does not provide enough model detail to reproduce it independently.

The two-part design raises a further interpretive issue. Part 1 supplies a blinded placebo comparison, whereas Part 2 is open-label and includes later treatment. Safety counts across those periods cannot be treated as if they came from the same randomized contrast. Design context is essential to avoid reading later observations as a direct extension of the blinded comparison.

Finally, the number of listed outcomes and analyses makes multiplicity and prespecification relevant. Without a reported hierarchy or adjustment, secondary analyses are more appropriately viewed as supporting or exploratory evidence. The registry record’s gaps on analysis planning and missing-data handling also show why transparent methods are necessary for judging the precision and credibility of a result.

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 primary comparison has broad confidence limits, so the estimated effect is imprecise. The registry reports 37 participants in the inclisiran arm and 19 in the placebo arm for the primary endpoint, but does not report the original sample-size rationale or whether the study was planned to detect a particular effect size. The enrollment figure alone cannot establish the adequacy of the design for the primary question.

The registry names ANCOVA but does not report the model covariates, diagnostic checks, or a detailed analysis plan. The method used for missing outcome data, sensitivity analyses, and treatment of protocol deviations is also not reported in the registry record. This makes it difficult to assess how robust the primary estimate is to analytic choices.

The primary endpoint is measured at Day 150. It does not summarize all later observations or establish effects on clinical events. The second part is open-label, and the registry’s description of the treatment sequence for participants initially assigned to placebo is incomplete. Thus, the later study period cannot be interpreted as a continuing blinded placebo comparison.

There are many listed outcome measures and analyses, but multiplicity handling is not reported. The registry also does not explain why denominators for the secondary threshold endpoint differ from the primary endpoint group counts. These omissions limit interpretation of secondary findings and prevent a complete assessment of missing observations. The record does not report enough information to determine the relationship of individual adverse events to treatment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH) — NCT03851705.
• Registry record last updated 2023-01-30; status last verified 2023-01.
• Results first posted 2022-11-10.
• 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 Phase III randomized, double-blind, parallel-group study of inclisiran in participants with homozygous familial hypercholesterolemia. The study had a double-blind placebo-controlled Part 1 and an open-label Part 2, with enrollment of 56. The recorded start date was 2019-02-06, and primary completion was 2020-03-02.

The primary endpoint was percent change in LDL-C from baseline to Day 150. The sponsor-reported ANCOVA comparison estimated a mean difference of -1.68, with a 95% confidence interval from -29.19 to 25.83 and a reported p-value of 0.905. The interval is broad and includes no difference, leaving the estimated effect uncertain.

The registry lists multiple secondary outcomes and safety results. Details of multiplicity control, missing-data handling, model specification, and sample-size justification are not reported in the registry record. These gaps constrain interpretation, particularly for secondary analyses and later open-label observations.