Study of Alirocumab (REGN727/SAR236553) in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) Undergoing Low-density Lipoprotein (LDL) Apheresis Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Alirocumab (REGN727/SAR236553) in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) Undergoing Low-density Lipoprotein (LDL) Apheresis Therapy (NCT02326220), a randomized phase 3 study. The primary outcome is Change in Standardized Rate of Apheresis Treatments From Week 7 to Week 18.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, parallel-group study sponsored by Regeneron Pharmaceuticals. The registry record gives enrollment as 62. Participants were assigned to placebo or alirocumab 150 mg every 2 weeks during the double-blind period. The record describes quadruple masking. It does not specify the identities of every role covered by that masking in the registry record.

The placebo and alirocumab groups were followed during the double-blind period, with injections scheduled every 2 weeks up to Week 16. The primary outcome window extended from Week 7 to Week 18 and was described as occurring before open-label treatment. The record separately describes open-label alirocumab 150 mg every 2 weeks beginning at Week 18 and continuing up to Week 76. These are different treatment periods, so the open-label group should not be treated as a third randomized comparison group.

The primary population was intent-to-treat: randomized participants were analyzed according to their assigned group. The posted primary outcome summaries include 21 participants in the placebo group and 41 in the blinded alirocumab group. The study’s original allocation rationale and sample-size justification are not reported in the registry record. The enrollment total alone does not establish how the trial’s design assumptions were selected.

The record identifies multiple secondary outcomes, including lipid measures at Week 6 and a standardized apheresis rate from Week 15 to Week 18. It reports 23 outcome measures and 7 analyses. The registry record does not describe whether all outcomes were included in a prespecified testing hierarchy, or whether the analyses were adjusted for testing multiple 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: Randomization was stratified according to the frequency of the apheresis procedure (every 7 or 14 days) and lipoprotein (a) (Lp \[a\]) levels (normal or elevated). Assignment to treatment arms was done using an Interactive Voice/Web Response System in 1:2 ratio to placebo or alirocumab 150 mg Q2W.

Double-blind Treatment Period

Reasons for not completing this period:

Open-label Treatment Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Primary intent-to-treat (ITT) population defined as all randomized participants and were analyzed according to the treatment group allocated by randomization.

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 randomized population.

6. Primary Endpoint

The registry lists the primary outcome as Change in Standardized Rate of Apheresis Treatments From Week 7 to Week 18, measured over Week 7 to Week 18 (before start of open-label treatment).

The primary endpoint was the change in standardized rate of apheresis treatments from Week 7 to Week 18, before the start of open-label treatment. The registry record defines the participant-level rate using the actual number of apheresis treatments received during that period relative to the number planned for the participant’s baseline schedule. The planned schedule was represented by 6 treatments for the every-2-week stratum and 12 for the weekly stratum.

Standardization is useful when participants follow different treatment schedules: it expresses treatment frequency in relation to the schedule each participant was expected to follow. The outcome is therefore not simply a raw count of procedures, and its interpretation depends on the baseline schedule used as the reference. A lower standardized rate means fewer actual treatments relative to the planned number during the specified period; the outcome itself does not measure LDL concentration or directly establish why treatment frequency changed.

The endpoint was chosen to address the study’s stated objective of evaluating apheresis-treatment frequency. The registry record does not report a separate explanation for choosing this endpoint over other clinical or laboratory measures, or further detail about how deviations from planned schedules were handled.

7. Results Posted in the Registry

• Alirocumab 150 mg Q2W (Double Blind Period): mean 0.13 versus 0.81 on control; difference -0.68 (95% CI -0.79 to -0.57), standardized effect d = -3.00; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percent Change From Baseline in Calculated LDL-C (Pre-apheresis) at Week 6

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Alirocumab 150 mg Q2W (Double Blind Period): mean -53.70 versus 1.60 on control; difference -55.30 (95% CI -62.87 to -47.73), standardized effect d = -3.80; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Alirocumab 150 mg Q2W (Double Blind Period) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change in Standardized Rate of Apheresis Treatments From Week 15 to Week 18

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Alirocumab 150 mg Q2W (Double Blind Period): mean 0.17 versus 0.77 on control; difference -0.61 (95% CI -0.78 to -0.44), standardized effect d = -1.86; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Alirocumab 150 mg Q2W (Double Blind Period) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Alirocumab 150 mg Q2W (Double Blind Period): mean -42.80 versus 1.20 on control; difference -44.00 (95% CI -51.18 to -36.82), standardized effect d = -3.25; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Alirocumab 150 mg Q2W (Double Blind Period) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes broadly point in a direction consistent with the primary group summaries. At Week 6, the posted lipid estimates for calculated LDL-C and Apo B are lower in the alirocumab group than in the placebo group. The Week 15 to Week 18 standardized apheresis-rate comparison also has a lower posted estimate in the alirocumab group. These measures relate to the primary question but are not interchangeable: the lipid outcomes concern laboratory measures at an earlier time, while the primary outcome concerns standardized treatment frequency over a specified interval.

The registry lists a range of additional lipid outcomes, including non-HDL-C, total cholesterol, and Apo A1, as well as thresholds for reductions in calculated LDL-C. Numerical results for those outcomes are not reported in the registry record. The record lists 22 secondary outcomes, but only a subset has numerical summaries in the analysis details available in the registry record. The direction of unreported outcomes should not be inferred from the outcomes with numerical summaries.

For the secondary analyses with reported model results, the registry gives p-values below < 0.001. Those results indicate evidence of group separation under the reported analyses, but the registry does not report a multiplicity adjustment or a testing hierarchy. When many outcomes are examined, the chance of at least one apparently significant result can increase unless the analysis plan accounts for multiple testing. Therefore, unadjusted secondary findings generally carry less confirmatory weight than a clearly designated primary outcome.

The secondary results can support a coherent description of what was measured during the trial, but they should be interpreted as additional evidence rather than independent confirmation of the primary result. Their different scales, time points, and analysis methods mean that consistency in direction is informative but does not make the outcomes equivalent. The registry record does not report enough detail to determine whether all planned secondary comparisons were analyzed or how the choice of reported secondary analyses was made.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percent Change From Baseline in Calculated LDL-C (Pre-apheresis) at Week 6
• Change in Standardized Rate of Apheresis Treatments From Week 15 to Week 18
• Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6
• Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) to Week 6
• Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 6
• Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) to Week 6
• Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6
• Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6

9. Statistical Interpretation

10. Statistical Methods Explained

The registry record’s primary analysis is described as ANCOVA, with a Hodges–Lehmann estimate of median difference. The recalculated comparison is an unadjusted difference between group means. These methods summarize the randomized groups in different ways, so their estimates need not match numerically or share the same direction convention. The reported primary analysis should be interpreted using the statistic and direction as described by the registry, rather than treating the recalculation as a replacement.

What does a mean difference describe?

A mean difference subtracts one group’s average from another’s. The recalculation defines the comparison as alirocumab relative to placebo, so the posted group means yield a negative estimate when the alirocumab mean is lower. This summary is easy to relate to the displayed group averages, but it does not account for covariates in the way an adjusted model may. It is also sensitive to the distribution of the outcome: a small number of unusual values can influence a mean.

The outcome is a continuous standardized rate, and the group summaries include standard deviations. A standard deviation describes spread among participant values within a group; it is not the uncertainty of the group mean. The standard error, by contrast, describes the estimated sampling uncertainty of a statistic. For some secondary outcomes, the record reports least-squares means with standard errors, which are model-based summaries rather than raw group means with standard deviations.

What does ANCOVA contribute?

ANCOVA is a regression approach that compares groups while accounting for covariates included in the model. The registry record identifies ANCOVA for the primary analysis, but it does not report the covariates, model specification, or handling of all model assumptions. Those details are not reported in the registry record. The presence of ANCOVA alone does not reveal which participant characteristics were included or the extent to which the estimate was adjusted.

The reported primary parameter is a Hodges–Lehmann estimate of median difference. In general, this is a location-shift summary based on pairwise differences between observations, rather than a subtraction of the two group means. A median-based summary can be less influenced by extreme observations than a mean, but it answers a different statistical question. The registry gives a confidence interval and p-value for this estimate, allowing the reported analysis to be read on its own terms.

Why distinguish reported and recalculated results?

The recalculated primary comparison is an unadjusted calculation from posted summary statistics. It is useful as a transparent check of the group means, but it is not the trial’s complete analysis plan or a reconstruction of the ANCOVA. The two estimates differ in both the summary statistic and analysis approach. Since the registry record does not mark a discrepancy, no conflict is asserted; nevertheless, the sponsor’s reported primary analysis remains the trial’s own inferential result, while the recalculation is a supplementary descriptive comparison.

For outcomes summarized by least-squares means, the recalculation uses posted estimates and uncertainty summaries. In the LDL-C and Apo B comparisons, the record identifies the spread as a standard error, not a standard deviation. The recalculated pooled spread is therefore approximate, rather than a direct pooled estimate from participant-level data. This matters because standard errors describe uncertainty in estimated means, while standard deviations describe participant-to-participant variability. A recalculation built from standard errors should not be presented as if it had access to raw observations.

What role do p-values play?

A p-value describes how incompatible the observed data are with a specified null hypothesis under the assumptions of the test. A small p-value is not the probability that the null hypothesis is true, nor does it measure the size or importance of an effect. For the primary outcome, both the registry analysis and the unadjusted recalculation report small p-values, but the registry analysis is the sponsor’s prespecified-style analysis as recorded; the detailed protocol plan is not reported in the registry record. The registry’s report of an analysis does not, by itself, establish the exact timing or prespecification of every decision.

As a general statistical point, continuous outcomes can be affected by skewness, outliers, and unequal variability. Model assumptions and diagnostic checks help determine whether an analysis is suitable. The registry record does not report diagnostic plots, residual checks, or sensitivity analyses for this endpoint, so those aspects cannot be evaluated from the record. This is not evidence that such checks were or were not performed.

As a general statistical point, over-dispersion is more often discussed for count outcomes when observed variability exceeds what a simple count model expects. Apheresis frequency is conceptually related to a count, but the primary endpoint is reported as a standardized continuous rate with means and standard deviations. The record does not describe a count model or an over-dispersion adjustment. It would therefore be inappropriate to assume that a particular count-model method was used.

11. Confidence Intervals and Precision

A confidence interval expresses a range of values compatible with the observed data under the assumptions of the analysis. It conveys uncertainty around an estimate, not a guarantee that the true value lies within that particular interval. Narrower intervals indicate greater statistical precision under the same analysis framework, while wider intervals indicate more uncertainty.

For the primary reported analysis, the estimated median difference was 0.750, with a 95% confidence interval from 0.667 to 0.833. The interval lies on the positive side of zero, and the reported p-value is p < 0.001. The statistic is the registry’s Hodges–Lehmann median-difference estimate from ANCOVA, not the unadjusted mean difference. The direction and scale should therefore be interpreted according to that reported statistic.

The recalculated mean difference is -0.678, with p < 0.001. Its direction follows the alirocumab-minus-placebo convention and the lower posted alirocumab mean. The recalculation’s confidence limits are not repeated because the recorded values have more than 3 decimal places. The sponsor’s reported interval and the recalculated estimate should not be combined into one interval or treated as estimates of precisely the same parameter.

The size of a confidence interval depends on the variability of the outcome, the amount of information in the groups, and the analysis method. The registry’s interval reflects its reported model and statistic; the unadjusted recalculation reflects a different calculation. Neither interval captures every source of uncertainty, such as uncertainty about generalizing to people outside the trial population or uncertainty about unreported model choices.

For the reported LDL-C and Apo B comparisons, the confidence intervals also exclude zero and the registry reports p-values below < 0.001. These intervals concern secondary outcomes and do not resolve the limitations of multiple testing or unreported analysis details. Statistical precision for an estimate is not the same as certainty about clinical meaning.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not a total sample size or a count of events. They are illustrations based on the observed treatment effect, not the original trial’s sample-size calculation. For the primary outcome, the planning illustration gives 2 participants per arm for 80% power and 3 participants per arm for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 4 participants per arm for 80% power and 5 participants per arm for 90% power. Planning for 50% of the observed effect gives 7 participants per arm for 80% power and 10 participants per arm for 90% power.

The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. In plain terms, the 80% power column describes an illustrative design with an 80% chance of detecting the assumed effect under those planning assumptions if that effect were present. The 90% column describes the corresponding design using a higher target chance of detection. Achieving a higher target generally requires more participants for the same effect.

Smaller effects require more participants to detect with the same target power. These calculations are not observed power: they are planning illustrations based on the effect observed in this trial, not a retrospective measure of whether the trial was adequately powered. The original design assumptions and sample-size justification are not reported in the registry record. The calculated illustrations should not be used to infer what the investigators planned before enrollment.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.678; pooled standard deviation σ = 0.226.
2. n = 2 × (1.96 + 0.842)² × 0.226² / -0.678² = 1.7, rounded up to 2 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.678                      # observed difference in means
sigma <- 0.226280799008665                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2326220)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 2 (80% power), 3 (90% power)
 75% of observed effect: n per arm = 4 (80% power), 5 (90% power)
 50% of observed effect: n per arm = 7 (80% power), 10 (90% power)
power.t.test: 3.1 
Simulated power at n = 2 per arm: 0.387 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry’s own primary analysis reports an ANCOVA result as a Hodges–Lehmann estimate of median difference: 0.750, with a 95% confidence interval from 0.667 to 0.833 and p < 0.001. The separate recalculation is an unadjusted mean difference of -0.678, with p < 0.001. The two estimates are not like-for-like: one is a median-difference estimate from the reported analysis, and the other compares posted means without the reported ANCOVA model.

The direction also uses different conventions. The recalculation is expressed as alirocumab minus placebo, giving a negative value because the alirocumab mean is lower. The registry’s positive median-difference estimate is reported in its own analysis and does not mean that the alirocumab group had the higher posted mean. The registry does not give a direction convention in the result description that would justify relabeling the sponsor estimate as the same contrast used in the recalculation.

Because the sponsor’s result is the trial’s reported analysis, it takes precedence as the primary inferential result. The recalculation is a check based on posted summary statistics and is useful for understanding the group means; it does not replace the reported model or recover its covariate adjustment. The record does not flag a discrepancy between the analyses.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary outcome and multiple secondary outcomes, but it does not report a multiplicity-control procedure, a hierarchy for testing outcomes, or a familywise error strategy. This information is important because testing many outcomes can raise the chance of obtaining one or more small p-values by chance, even when each individual test uses a conventional significance threshold. Without a reported adjustment or hierarchy, secondary p-values should be read as nominal evidence rather than as proof that every secondary finding is independently confirmatory.

The record gives an intent-to-treat definition for the primary population: all randomized participants are analyzed according to their assigned treatment group. This approach preserves the randomized comparison in the analysis definition. The record does not report details about missing outcome values, exclusions from particular analyses, imputation, or sensitivity analyses. Those details are not reported in the registry record, so the effect of missing data on the estimates cannot be assessed from the listed summaries.

The registry describes the primary method as ANCOVA but does not provide the model covariates or other specification details. It also does not report the full statistical analysis plan, interim-analysis procedures, or the timing of decisions about outcomes. These details are not reported in the registry record. Their absence from the record should not be read as evidence that no such plans or procedures existed.

For the secondary lipid outcomes, the record reports least-squares means and standard errors, but does not provide enough information to reconstruct each model or assess its assumptions. The primary endpoint’s reported median-difference analysis likewise cannot be fully reproduced from the group summaries alone. Participant-level data and additional analysis documentation would be needed to examine missingness, model fit, and alternative analytic choices.

16. 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: acute myocardial infarction (4.9%), angina pectoris (4.8%), sinus bradycardia (4.8%), shunt thrombosis (4.8%), myocardial ischaemia (3.4%).

The registry lists serious adverse events and other adverse events separately for the double-blind placebo group, the double-blind alirocumab group, and an open-label alirocumab group. Serious adverse events affected 2 participants in the placebo group, 4 in the blinded alirocumab group, and 1 in the open-label group. The corresponding at-risk counts are 21, 41, and 29. These are group-specific counts, not a randomized comparison across all three periods: the open-label group belongs to a different treatment period.

Other adverse events affected 10 participants in the placebo group, 22 in the blinded alirocumab group, and 2 in the open-label group. The record reports 0 deaths in each group. These counts alone do not describe event severity beyond the serious-versus-other distinction, timing, duration, or relationship to treatment. Nor do they establish that an event was caused by the assigned treatment.

The registry lists several serious-event terms with percentages, including acute myocardial infarction, angina pectoris, sinus bradycardia, shunt thrombosis, myocardial ischaemia, and peripheral artery restenosis. The denominators and event-level details for those percentages are not described in the summary. Small group counts and the separate open-label period limit direct comparisons. The safety figures should be read as descriptive registry counts, not as a complete assessment of comparative safety.

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

The primary result describes a difference in standardized apheresis-treatment frequency between the randomized groups during the Week 7 to Week 18 window. The registry’s reported analysis estimates a median difference of 0.750, with a 95% confidence interval from 0.667 to 0.833 and p < 0.001. The posted means are lower in the alirocumab group than in the placebo group. The recalculated mean difference of -0.678 expresses that mean comparison with alirocumab minus placebo.

This result does not mean that every participant changed apheresis frequency by the same amount. Group-level summaries do not show the distribution of individual responses, the number of people who changed their schedule, or why any schedule changed. The endpoint is standardized against each participant’s planned schedule, so it should not be interpreted as a raw treatment count or as a direct measure of cholesterol concentration.

The outcome also does not establish that alirocumab has a particular effect in people who do not receive LDL apheresis, or in people with conditions other than HeFH. The result pertains to the randomized population and the recorded treatment period. The open-label phase is described separately and is not the blinded randomized comparison underlying the primary endpoint.

A small p-value is not proof of clinical importance, and a confidence interval does not remove uncertainty about the study’s analysis choices, missing data, or generalizability. The registry record does not report enough detail to evaluate all of those issues. The results should be read as evidence about the measured endpoint under this trial’s conditions, rather than as a broad conclusion about treatment for every person with HeFH.

18. Why This Trial Matters Statistically

This trial is statistically notable for asking a treatment-frequency question in a population already receiving apheresis, rather than relying only on a laboratory measure. The primary endpoint standardizes actual apheresis treatments against each participant’s established schedule. That definition makes the baseline schedule central to interpretation and helps distinguish this outcome from a simple count of procedures.

The randomized, blinded, placebo-controlled parallel-group design provides a direct comparison during the double-blind period. The primary intent-to-treat population is defined according to randomized assignment, which keeps the analysis aligned with the randomized groups. The registry’s reported ANCOVA analysis and the unadjusted mean recalculation illustrate why the choice of estimand and model matters: two valid summaries can answer related but different statistical questions and use different directional conventions.

The trial also illustrates the need to keep primary and secondary evidence distinct. Lipid outcomes and a later apheresis-rate measure can add context, but they differ in measurement, timing, and analysis. Without reported multiplicity procedures, secondary p-values warrant more caution than the designated primary result. Similarly, planning illustrations derived from the observed effect are not a substitute for the trial’s original design assumptions.

Finally, safety summaries require attention to period and group. The open-label data are not a third randomized arm, and descriptive event counts should not be interpreted as randomized treatment effects. These distinctions make the registry record useful for statistical learning: design, endpoint definition, analysis method, and reporting context all shape what a numerical result can support.

19. 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 endpoint depends on a participant’s established apheresis schedule, and the registry record does not describe how changes to that schedule, missed procedures, or deviations from plans were handled. It gives the normalization definition but not enough detail to independently evaluate the underlying participant-level counts or their distribution.

The record reports the primary analysis method and estimate but does not specify the ANCOVA covariates, model diagnostics, or sensitivity analyses. The recalculation from summary statistics is unadjusted and does not reproduce the sponsor’s model. For some secondary endpoints, standard errors are used in the posted summaries; recalculations based on these are approximate rather than calculations from raw participant-level observations.

Details about missing data, exclusions in individual analyses, and imputation are not reported in the registry record. Neither is a multiplicity strategy for the many outcomes listed. These omissions limit assessment of how robust the secondary findings are and how missing observations may affect the estimates.

The record describes a blinded randomized period and a later open-label period. The open-label results do not provide a concurrent placebo comparison and should not be combined with the blinded comparison as if all groups were randomized in the same way. The reported adverse-event counts are descriptive and do not include all event-level information needed to judge timing, treatment relationship, or exposure-adjusted risk.

Generalizability is also bounded by the population and treatment setting recorded: participants had HeFH and were receiving weekly or bi-weekly LDL apheresis. The registry record does not provide information that would support extending the findings to other populations or treatment contexts.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study of Alirocumab (REGN727/SAR236553) in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) Undergoing Low-density Lipoprotein (LDL) Apheresis Therapy — NCT02326220.
• Registry record last updated 2020-05-01; status last verified 2020-04.
• Results first posted 2020-05-01.
• 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.

23. Record Summary

NCT02326220 records a completed, randomized, double-blind, placebo-controlled, parallel-group phase 3 study of alirocumab in participants with HeFH undergoing LDL apheresis. The record lists enrollment of 62 and describes blinded treatment with alirocumab 150 mg every 2 weeks or placebo. The primary endpoint was the standardized rate of apheresis treatments from Week 7 to Week 18.

The sponsor’s reported primary analysis used ANCOVA and gave a Hodges–Lehmann median-difference estimate of 0.750, with a 95% confidence interval from 0.667 to 0.833 and p < 0.001. The unadjusted recalculation of the posted means is -0.678, with p < 0.001; it is a different statistical summary and does not replace the reported analysis. The record also describes secondary lipid and apheresis outcomes, a later open-label period, and adverse-event counts. Details of multiplicity handling, missing-data methods, and the original sample-size justification are not reported in the registry record.