A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD) (NCT05088460), a randomized phase 2 study. The primary outcome is Percent Change From Baseline to Week 12 in Fasting Serum Triglyceride (TG) (Cohort A).

2. Clinical Question

The study also included objectives relating to hyperglycemia, liver fat, hunger, safety and tolerability, drug concentration over time, and immunogenicity. These objectives extended to Cohort B and, for some assessments, to the combined cohorts. The primary triglyceride question is narrower: it concerns Cohort A and the week-12 change in fasting serum triglycerides.

3. Trial Design

This was a randomized, quadruple-masked, parallel-group phase 2 study of REGN4461 and matching placebo. The registry lists enrollment as 20 and the status as terminated. The recorded study start was 2022-02-28, and the primary completion date was 2023-12-13. The reason for termination is not reported in the registry record.

Participants were classified by baseline leptin level. Cohort A comprised patients with baseline leptin <8.0 ng/mL, while Cohort B comprised patients with baseline leptin from 8.0 to ≤20.0 ng/mL. The primary objectives were evaluated for Cohort A only. They concerned fasting triglycerides among participants with elevated baseline fasting triglycerides and hyperglycemia among participants with elevated baseline HbA1c.

One arm was randomized to placebo for 12 weeks and then crossed over to REGN4461 for 12 weeks. The other arm received REGN4461 for 24 weeks. Thus, the initial period supplies a concurrent placebo and active-treatment comparison, while the later period includes REGN4461 exposure in both arms. The registry record does not report the randomization procedure, allocation ratio, or further details of the masking process.

The primary endpoint was percent change in fasting serum triglycerides from baseline to week 12 in Cohort A. The listed analysis population was the Full Analysis Set: randomized participants who received any study drug in the double-blind treatment period and had at least one post-baseline assessment. For this outcome, the registry defines the analyzed number as the number evaluable for the measure. The reported analyzed counts were 5 in the placebo-to-REGN4461 arm and 6 in the REGN4461-to-REGN4461 arm.

Secondary outcomes included triglyceride, HbA1c, and fasting-glucose changes at week 12 and week 24, with some outcomes separated by arm or cohort. The registry lists 19 outcome measures and 17 posted secondary outcomes. The study status and these listed outcomes do not establish that every planned objective was completed or analyzed.

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 66 participants were screened, of whom 20 were randomized and received study treatment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) included all randomized participants who received any study drug in the double-blind treatment period (DBTP) and had at least 1 post-baseline assessment. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.

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: The double-blind safety analysis set (DB SAF) included all randomized participants who received any study drug during the double-blind treatment period (DBTP).

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline to Week 12 in Fasting Serum Triglyceride (TG) (Cohort A), measured over Baseline to week 12.

The primary endpoint is percent change from baseline to week 12 in fasting serum triglycerides for Cohort A. The registry describes this outcome for participants whose baseline fasting triglycerides were >200 mg/dL and whose baseline leptin was <8.0 ng/mL. It is a continuous measure: each participant’s change is expressed relative to that participant’s baseline, and the arm-level result is reported as a mean with a standard deviation.

Percent change puts change in relation to the baseline value rather than expressing it in the original triglyceride units. A negative mean indicates that the average measured value at follow-up was below baseline on the percent-change scale. This summary does not show how every participant changed; the standard deviation describes variation around the arm mean.

Fasting triglycerides were selected as a primary measure because the registry identifies elevated fasting triglycerides as a metabolic abnormality of interest in this population. That explains the endpoint’s clinical-study role, but the record does not report the rationale used to choose this endpoint over other measures, a target difference considered meaningful, or a sample-size justification.

The posted means are -11.3% for the placebo-to-REGN4461 arm and -38.97% for the REGN4461-to-REGN4461 arm. Their standard deviations are 46.31 and 17.0, respectively. These are descriptive results for the analyzed participants; the registry record does not report a confidence interval or a formal statistical comparison for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous outcome as a mean and standard deviation. Understanding what each summary represents helps distinguish the observed data from an inferential comparison.

What does the mean represent?

For a continuous outcome, the mean is the arithmetic average of the observations included in the analysis. Here the measure is percent change in fasting serum triglycerides from baseline to week 12. A negative arm mean means that the average percent change was below baseline. It does not mean that every participant had a decline, nor does it describe the shape of the individual results.

The registry reports a mean of -11.3% for the placebo-to-REGN4461 arm and -38.97% for the REGN4461-to-REGN4461 arm. Those values are the arm summaries for the endpoint population. They should be distinguished from a direct estimate of the effect of assignment to REGN4461 relative to placebo. No such between-arm estimate is reported for this endpoint.

What does the standard deviation describe?

A standard deviation describes how spread out observations are around their mean. The reported standard deviations are 46.31 and 17.0. They convey variability in individual percent changes, rather than precision of the mean. A standard error or confidence interval would address uncertainty about an estimate; the registry does not report either for this primary endpoint.

When participant outcomes are highly variable, the mean alone may not represent a typical individual response. A large standard deviation relative to the mean can signal substantial dispersion, but it does not reveal whether the data are symmetric, contain outliers, or have distinct subgroups. Those features require participant-level data or additional summaries, which are not reported in the registry record.

Why is a confidence interval useful?

In general, a confidence interval expresses uncertainty around an estimate under a specified statistical procedure. For a treatment comparison, an interval can show which effect sizes are reasonably compatible with the data and model. It also communicates precision more directly than a p-value alone. No confidence interval is reported for the primary endpoint, so the precision of the arm means and any treatment contrast cannot be assessed from the registry summary.

Likewise, a p-value would address the compatibility of data with a specified null hypothesis under a statistical model, not the size or clinical importance of an effect. No p-value or formal between-arm test is reported for the primary endpoint. The posted means should therefore be read as descriptive observations, not as evidence from a reported significance test.

What is the role of the analysis population?

The Full Analysis Set is described as randomized participants who received any study drug during the double-blind treatment period and had at least one post-baseline assessment. The registry further notes that the analyzed number for this outcome is the number evaluable for the measure. The reported endpoint counts are 5 in the placebo-to-REGN4461 arm and 6 in the REGN4461-to-REGN4461 arm.

This definition is narrower than a statement that every randomized participant contributed an endpoint value. The record does not report the number excluded from this endpoint analysis, reasons for missing assessments, or how missing week-12 values were handled. Those details matter because the analyzed participants may not represent everyone randomized if evaluability is related to outcome or treatment experience.

How does the treatment schedule affect comparison?

Randomization creates the basis for comparing assigned groups, while masking is intended to limit certain biases in treatment delivery and outcome assessment. The registry identifies the study as randomized and quadruple-masked but does not describe the exact implementation of either process. During the first 12 weeks, the arms had different assigned treatments. After that, the placebo arm crossed over to REGN4461. Outcomes measured after crossover cannot be interpreted as a simple ongoing comparison between REGN4461 and placebo, because both arms then received REGN4461.

What can planning calculations say?

In general, a sample-size planning illustration describes the number of participants that a hypothetical future study might require under stated assumptions. The registry’s stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such planning values are not observed trial outcomes and are not observed power. They do not show that this trial was designed with those assumptions. The trial’s own sample-size justification and statistical design calculations are not reported in the registry record.

Over-dispersion, in general, means that observed variability is greater than a model assumes. When that occurs, standard errors from an inadequately fitting model may be too small, making uncertainty appear less than it is. The registry reports standard deviations but does not report a model, variance assumption, or an over-dispersion assessment for this endpoint. No claim about whether over-dispersion occurred can be made from the posted summaries.

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("Arm 1 Cohort A: Placebo to REGN4461", "Arm 2 Cohort A: REGN4461 to REGN4461")
n   <- c(5, 6)
m   <- c(-11.3, -38.97)
sp  <- c(46.306, 16.998)
sd  <- sp      # posted standard deviations
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  Arm 1 Cohort A: Placebo to REGN4461  5  -11.300  46.306  -68.796  46.196
CARM  Arm 2 Cohort A: REGN4461 to REGN4461  6  -38.970  16.998  -56.808  -21.132

11. Multiplicity, Missing Data and Analysis Populations

The study includes multiple objectives and outcome measures. Primary objectives applied to Cohort A and included fasting triglycerides and hyperglycemia; secondary objectives covered triglycerides, glycemic measures, liver fat, hunger, safety and tolerability, drug concentration, and immunogenicity across specified cohorts. The registry lists 19 outcome measures and 17 posted secondary outcomes. Considering multiple outcomes or subgroups can increase the chance of at least one apparently notable result when many statistical tests are performed.

Whether any multiplicity adjustment was planned or applied is not reported in the registry record. The record also does not report a statistical analysis plan, a hierarchy for testing outcomes, or which outcomes were designated for confirmatory inference. Consequently, no adjustment—or lack of adjustment—should be assumed for secondary findings. The primary endpoint summary itself has no reported p-value or confidence interval.

The Full Analysis Set definition requires randomization, receipt of any study drug during the double-blind treatment period, and at least one post-baseline assessment. The outcome-specific analyzed number is the number evaluable for that measure. The primary endpoint counts are 5 and 6. The record does not report the number of missing values at each time point, reasons for missingness, imputation procedures, sensitivity analyses, or whether the analysis included participants in accordance with their randomized assignment in all circumstances.

Missing-data methods matter because an analysis based only on evaluable observations can be biased if the probability of having a measured outcome is related to the outcome itself or to treatment experience. This is a general statistical concern, not a claim that such bias occurred in this study. Without the missing-data details, the effect of any unavailable observations on the reported means cannot be assessed.

The registry reports zero analyses. That means formal analysis results beyond the posted descriptive outcome values are not included in the registry record; it does not establish that no analyses were conducted elsewhere. The sponsor’s analytic approach, planned handling of multiplicity, and study-specific sample-size justification are 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: pancreatitis acute (25.0%), hyperglycaemia (20.0%), angina pectoris (16.7%), back pain (16.7%), hypertension (16.7%).

The registry separates serious adverse events during the double-blind treatment period from those during the subsequent period. Each group gives the number at risk and the number affected. For Cohort A during the double-blind period, the placebo group had 1 serious adverse event among 6 at risk, and the REGN4461 group had 1 among 6. For Cohort B, the placebo group had 1 among 4, while the REGN4461 group had 0 among 4.

During the subsequent period, the Cohort A placebo-to-REGN4461 group had 1 serious adverse event among 5 at risk, and the REGN4461-to-REGN4461 group had 1 among 6. In Cohort B, the placebo-to-REGN4461 group had 0 among 3, and the REGN4461-to-REGN4461 group had 0 among 4. The registry lists 0 deaths in each of these groups.

These are group-specific counts, not a single combined estimate. The groups relate to different cohorts and treatment periods, and exposure changes after crossover. They should not be added together to create an overall rate or interpreted as directly comparable without accounting for those differences. The registry lists pancreatitis acute (25.0%), hyperglycaemia (20.0%), angina pectoris (16.7%), back pain (16.7%), and hypertension (16.7%) among the top serious terms, but those percentages do not provide a complete account of event timing or exposure.

Counts of people affected do not by themselves establish that an event was caused by study treatment. The registry record does not report enough detail to assess event adjudication, duration, severity beyond serious-event classification, or causal attribution.

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

The primary result describes mean percent changes in fasting serum triglycerides over the first 12 weeks among evaluable Cohort A participants who met the baseline triglyceride and leptin criteria. The placebo-to-REGN4461 arm had a mean change of -11.3%, with a standard deviation of 46.31; the REGN4461-to-REGN4461 arm had a mean change of -38.97%, with a standard deviation of 17.0. The analyzed counts were 5 and 6.

These summaries do not by themselves show how precise the arm means are, whether the arms differed beyond what could be due to chance, or whether any difference is clinically meaningful. The registry does not report a confidence interval, formal comparison, or p-value for this endpoint. Nor does an arm mean show the distribution of individual outcomes: people within the same arm may have had quite different changes.

The result is specific to a selected subgroup with baseline leptin <8.0 ng/mL and fasting triglycerides >200 mg/dL. It should not be generalized automatically to Cohort B, participants without elevated baseline triglycerides, or all adults with familial partial lipodystrophy. The registry does not report outcome estimates for those populations in the primary endpoint record.

The schedule also limits what can be inferred after week 12. The placebo arm crossed over to REGN4461, so later measurements compare different treatment histories rather than maintaining a placebo group. Secondary outcomes can describe the listed time points and groups, but the registry’s outcome titles alone do not provide estimates or support conclusions about those outcomes.

Finally, termination is a study status, not an explanation of the endpoint findings. The reason for termination and whether the study stopped as planned are not reported in the registry record. These results should be understood as the posted summaries, without assuming the reason for termination or inferring effects beyond the observations and analyses that are reported.

14. Why This Trial Matters Statistically

This trial illustrates why a numerical result needs its population, endpoint definition, and analysis context alongside the mean. The primary outcome is not a general measure of metabolic health: it is percent change in fasting serum triglycerides from baseline to week 12 among Cohort A participants with elevated baseline fasting triglycerides. The baseline leptin criterion further defines the group to which the result applies.

The reported means are accompanied by standard deviations, which show considerable variation in the observed changes, particularly in the placebo arm. A mean difference without an uncertainty interval or formal comparison cannot establish how precisely the groups differ. This is especially important when the endpoint counts are 5 and 6: descriptive arm summaries may be sensitive to individual observations, and uncertainty should be made explicit rather than inferred from the means alone.

The crossover schedule is another statistical feature with practical consequences. The placebo comparison is available during the first 12 weeks; after crossover, both arms receive REGN4461. Clear separation of the randomized comparison from later follow-up is necessary when interpreting outcomes at different time points.

The registry also lists numerous secondary outcomes across cohorts and treatment periods. Without a reported testing hierarchy or multiplicity approach, readers cannot tell which findings, if any, were intended to support confirmatory conclusions. Likewise, without details of missing-data handling, the relationship between the defined analysis population and all randomized participants remains uncertain.

These features make the record useful for understanding the scope and limits of the posted data. They also show why a small descriptive dataset should not be reduced to a single comparison of means: design, population selection, variability, missingness, and the availability of inferential statistics all shape the interpretation.

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 endpoint is available for a restricted population: Cohort A participants with baseline leptin <8.0 ng/mL and fasting triglycerides >200 mg/dL. The reported analyzed counts are 5 and 6. This limits the breadth of inference and makes the descriptive estimates vulnerable to the influence of individual observations.

The registry record reports arm means and standard deviations but no confidence intervals, p-values, or formal between-arm estimate for the primary outcome. It also does not report individual participant data, distributional summaries, or an analysis model. The observed standard deviations show variability, but they cannot substitute for an uncertainty interval around the treatment contrast.

The record does not report the number or reasons for missing endpoint assessments, how missing data were handled, or sensitivity analyses. Although the Full Analysis Set definition is stated, the outcome-specific count is based on evaluability. It is therefore not possible to assess the effect of incomplete observations on the reported summaries.

The study includes multiple secondary outcomes and cohort-specific objectives, but the statistical plan and multiplicity handling are not reported in the registry record. The stated sample-size planning assumptions are not a report of the trial’s own design justification, and that justification is not reported. The reason for termination is also not reported, so the status cannot be interpreted as evidence about the endpoint results or the conduct of the study.

Finally, the treatment crossover means placebo exposure ended at week 12. Later outcomes do not maintain a concurrent placebo comparison. The registry record does not provide further analysis details that would resolve these limitations.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD) — NCT05088460.
• Registry record last updated 2025-10-16; status last verified 2025-08.
• Results first posted 2025-07-02.
• 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 randomized, quadruple-masked, parallel-group phase 2 study of REGN4461 in adults with familial partial lipodystrophy and metabolic abnormalities. Enrollment is listed as 20, and the study status is terminated. One arm received placebo for 12 weeks before crossing over to REGN4461; the other received REGN4461 for 24 weeks.

The primary endpoint was percent change in fasting serum triglycerides from baseline to week 12 in Cohort A participants with baseline leptin <8.0 ng/mL and fasting triglycerides >200 mg/dL. The reported means were -11.3% and -38.97%, with standard deviations of 46.31 and 17.0 and analyzed counts of 5 and 6. No formal comparison, confidence interval, or p-value is reported for this endpoint.

The record lists 19 outcome measures and 17 posted secondary outcomes. The reason for termination, statistical analysis plan, multiplicity approach, and missing-data methods are not reported in the registry record.