Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity (NCT04966741), a randomized phase 3 study. The primary outcome is Percentage of Participants With Greater Than or Equal to (≥) 0.2 Reduction of BMI Z-Score From Baseline to Week 52.

2. Clinical Question

3. Trial Design

This was a phase 3, multicenter, 1-year, open-label study of setmelanotide in pediatric participants aged 2 to <6 years with rare genetic causes of obesity. The registry lists the study as completed, with an enrollment of 12. It records a start date of 2022-03-08 and a primary completion date of 2023-09-18.

The registry lists two groups in the posted primary results: a PPL group, comprising participants with POMC, PCSK1 or LEPR biallelic mutations, and a BBS group. Both groups received setmelanotide; the record does not describe a placebo or no-treatment arm. The PPL group had 7 participants in the primary result, and the BBS group had 5. These group-specific figures should not be interpreted as evidence of random allocation between treatment and control.

Allocation is classified as randomized in the registry, while masking is listed as none and the model as parallel. The record does not explain the randomization procedure, the allocation process, or whether randomization concerned assignment to any group. Those details are not reported in the registry record. The study was open-label, so participants and study personnel were not masked according to the registry classification.

The intervention descriptions specify daily subcutaneous setmelanotide injections over 52 weeks and dose escalation if tolerated. The available descriptions do not give the complete dosing information, including all details for the PPL group, so the regimen should not be elaborated beyond what is recorded. The study also listed safety, growth-related and developmental measures among its outcomes. The registry lists 7 secondary outcomes posted, but does not provide numerical results for those outcomes in the record summarized by the primary response results.

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: Of the 13 participants screened, 12 participants were enrolled in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety analysis set included all participants who received at least 1 dose of study drug.

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 safety analysis set included all participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Greater Than or Equal to (≥) 0.2 Reduction of BMI Z-Score From Baseline to Week 52, measured over Baseline up to Week 52.

The primary endpoint is the percentage of participants whose BMI Z-score decreased by at least 0.2 from baseline to Week 52. A responder is defined by that threshold; the endpoint therefore reports how many participants met a specified change criterion as a percentage of the group, rather than the average change in BMI Z-score.

BMI is calculated from weight and height. A BMI Z-score expresses a participant’s BMI relative to a reference population matched for age and sex, in standard deviation units. The registry says the scores used the World Health Organization’s Child Growth Standards 2007. A score of 0 corresponds to the reference mean; a lower score indicates a lower BMI relative to that reference. The endpoint uses change from baseline to address whether the score moved downward over the study period, while the responder threshold distinguishes changes meeting the stated criterion from smaller changes.

A threshold-based endpoint can be clinically and statistically easier to interpret as a proportion meeting a defined response criterion, but it also discards information about the size of changes beyond that cutoff. Participants with different amounts of reduction may count equally as responders, while a participant just short of the threshold is counted as a nonresponder. The posted results therefore describe the frequency of meeting the criterion, not the distribution of individual changes or the mean change in BMI Z-score.

The endpoint timeframe is baseline up to Week 52. Baseline is defined in the record as the most recent measurement before the first study-drug administration. The stated analysis population is the safety analysis set, defined as all participants who received at least one dose of study drug.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary response endpoint. Each participant is classified according to whether their BMI Z-score decreased by at least 0.2 from baseline to Week 52. The reported percentage is the proportion of participants classified as responders within each group. This differs from an endpoint based on a mean change: a mean uses the magnitude of each observed change, whereas a responder endpoint reduces each participant’s result to whether the stated threshold was reached.

What does the response percentage describe?

The response percentage describes the observed share of the analysis group meeting the endpoint definition. The PPL estimate is 85.7%, and the BBS estimate is 80.0%. These are descriptive estimates for the groups reported in the registry. They are not treatment-versus-control effects, because both groups received setmelanotide and no separate untreated or placebo group is described among the posted results.

The outcome record defines the analysis population as the safety analysis set: all participants who received at least one dose of study drug. This population definition matters because it identifies who is included in the reported endpoint analysis. The registry does not give further details about how participants without a Week 52 measurement, if any, were handled. Missing-data procedures are not reported in the registry record.

What does the confidence interval add?

A point estimate gives one summary value, while a confidence interval conveys how uncertain that estimate is under the statistical method used. The PPL estimate has a 95% confidence interval of 54.1% to 100.0%; the BBS estimate has a 95% confidence interval of 28.4% to 99.5%. The intervals are broad, so the posted estimates do not pin down the response proportions precisely. The registry does not state the interval calculation method, whether any adjustment was used, or whether the intervals were prespecified.

As a general statistical explanation, an interval for a percentage can be wide when the group is small, particularly when the observed percentage is near an endpoint of the possible range. Different interval methods can behave differently in that setting. The registry does not identify which method produced these intervals, so the calculation should not be inferred from the displayed values alone.

Why is a group comparison not available?

The outcome figures are presented separately by genetic-condition group. A formal comparison would require a specified contrast, such as a difference in response proportions, along with its uncertainty and a method for testing or estimating it. That comparison is not reported in the registry record. It would be inappropriate to calculate a new contrast from the group percentages and treat it as the trial’s analysis.

More generally, comparing two point estimates informally is not equivalent to a statistical test. The observed percentages can differ even when the data are too imprecise to support a reliable conclusion about a difference. Here, the confidence intervals are broad and overlap, and no between-group analysis is posted. The registry’s randomized allocation classification does not supply the missing details about randomization or establish a randomized comparison between these two condition groups.

What can be learned from a threshold endpoint?

A threshold endpoint can make a result interpretable as the proportion meeting a prespecified criterion. However, it does not preserve the full scale of participant-level change. A participant whose score decreases by more than the threshold and a participant whose score decreases by exactly the threshold are both counted as responders. A participant whose change falls just short is counted as a nonresponder. The response percentages do not show the distribution of changes, baseline values, or the average change.

The registry also lists a secondary outcome for mean absolute change from baseline in BMI Z-score and other growth and developmental measures. Numerical results for those secondary outcomes are not included in the record summarized by the posted primary results. The registry lists 7 secondary outcomes posted, but the existence of those outcomes does not supply their estimates or uncertainty.

What is not a trial analysis?

Any sample-size illustration based on an observed effect is a planning exercise, not an observed-power result. The registry does not report the trial’s sample-size justification or the assumptions used to choose its enrollment. The design details for interim analyses, stopping rules, covariate adjustment, and statistical analysis procedures are not reported in the registry record. In general, over-dispersion is relevant when observed variability in count or proportion data exceeds what a chosen statistical model assumes; it can affect uncertainty estimates. The record does not state that such a model was used for this endpoint, so no adjustment for over-dispersion can be claimed.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Setmelanotide: PPL Group", "Setmelanotide: BBS Group")
n      <- c(7, 5)
events <- c(6, 4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Setmelanotide: PPL Group  7  6  85.7  42.1  99.6  48.7  97.4  47.3  96.8
ARM  Setmelanotide: BBS Group  5  4  80.0  28.4  99.5  37.6  96.4  35.9  95.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 secondary outcomes in addition to the primary endpoint. These include mean absolute change in BMI Z-score, change in the percent of the 95th percentile of BMI, bone age, developmental questionnaire shifts, body weight change, and treatment-emergent adverse events. The primary endpoint is defined as the percentage meeting the BMI Z-score response threshold by Week 52.

When a study examines multiple outcomes or multiple hypotheses, the chance of at least one false-positive finding can increase if each is assessed without accounting for multiplicity. Statistical strategies can define one primary question, adjust significance thresholds, or otherwise control the interpretation of multiple tests. This is general statistical context; the multiplicity strategy for this study is not reported in the registry record. The record does not state whether secondary outcomes were adjusted, treated as exploratory, or tested within a prespecified hierarchy.

Missing-data handling is also not reported in the registry record. The primary outcome specifies an analysis population consisting of participants who received at least one dose of study drug, but that definition alone does not explain how an unavailable Week 52 measurement would be treated. The record does not report imputation, a missing-data sensitivity analysis, or whether all participants in that population had endpoint measurements.

The registry lists 7 secondary outcomes posted, but numerical results for them are not included with the primary response figures. The record also does not provide a detailed statistical analysis plan, the procedures for interim analyses, or the basis for sample-size selection. These omissions limit assessment of how the reported endpoint relates to the full set of planned analyses.

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 2% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts separately for the PPL and BBS groups. No serious adverse events are recorded in either group: 0 among the 7 participants at risk in the PPL group and 0 among the 5 participants at risk in the BBS group. Deaths are recorded as 0 in each group. These counts describe what was reported during the study; they do not establish that serious events are impossible or that the treatment caused or prevented any event.

For other treatment-emergent adverse events, the registry records 7 affected participants among 7 at risk in the PPL group and 5 affected participants among 5 at risk in the BBS group. The record does not provide a list of the most common serious-event terms; no top serious terms are listed. These all-cause counts should not be read as evidence that every event was caused by setmelanotide. Attribution details, event types, timing, severity distributions and exposure-adjusted rates are not reported in the registry record.

Zero observed serious events in groups of this size leaves considerable uncertainty about the frequency of uncommon events. A count of zero is not proof of zero risk. Safety counts also do not provide a comparison with an untreated group, since no such comparator is described among these posted arms. The registry record should therefore be read as a report of observed event counts in this study, not as a complete characterization of safety.

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

The posted results show that a high percentage of participants in each reported group met the study’s defined BMI Z-score response criterion by Week 52: 85.7% in the PPL group and 80.0% in the BBS group. The corresponding 95% confidence intervals are broad, so the group-specific response proportions remain uncertain. The result is a threshold-based summary of participants’ changes, not a description of average change or the range of individual responses.

The findings do not establish a difference between the PPL and BBS groups. The registry does not report a formal comparison, and both groups received setmelanotide. The record therefore does not show how these outcomes compare with a placebo group, no treatment, or an alternative intervention. The registry’s classification of allocation as randomized does not, by itself, clarify the allocation procedure or identify a randomized treatment-control contrast in the posted results.

The open-label design means masking was not used. This is relevant when considering outcomes that may be affected by study conduct, measurement, or expectations, although BMI itself is calculated from height and weight measurements. The record does not give enough detail to assess measurement procedures, missing measurements, or any analysis adjustments.

The response criterion captures whether a participant crossed the specified threshold; it does not indicate the size of the reduction among responders or the experience of participants who did not meet the criterion. Results for the listed secondary outcomes are not reported with these primary figures. The safety data record no serious adverse events or deaths in either group, while other treatment-emergent adverse events were recorded for all participants in each group. These counts are limited by the small groups and do not establish comparative safety or causation.

Overall, the registry reports encouragingly high observed response percentages within this study, but precision is limited and causal interpretation is constrained by the absence of a reported concurrent comparator and by the open-label design. The results should be understood as findings in the enrolled study groups, not as a definitive estimate for every child with these conditions.

14. Why This Trial Matters Statistically

This study addresses a population defined by rare genetic causes of obesity in very young children. Separating results into PPL and BBS groups acknowledges that the enrolled participants did not all share the same genetic condition. Statistically, that distinction is important: a single pooled percentage could conceal differences in the groups, while separate estimates remain highly uncertain when group sizes are small.

The endpoint illustrates the interpretive trade-off involved in responder analyses. A threshold can provide a clear description of the proportion meeting a stated criterion, but it compresses the underlying continuous change into a yes-or-no classification. The reported percentages answer the question of how often the criterion was met; they do not tell how large the changes were or how responses varied across participants.

The wide confidence intervals are central to interpretation. They show that the observed response percentages do not precisely determine the underlying group response proportions. Reporting uncertainty alongside point estimates is especially important when the study groups are small. The results should not be reduced to the point estimates alone or treated as a precise forecast for other participants.

The registry’s randomized allocation label and open-label classification also illustrate why design details matter. The posted primary results compare two condition groups receiving the same intervention, but the randomization procedure and its role are not explained. Without a clearly reported treatment-control contrast, these outcome proportions cannot isolate an effect attributable to setmelanotide.

Finally, the record distinguishes efficacy-oriented outcomes from safety counts but does not provide full results for the listed secondary measures or detailed statistical procedures. That limits broader assessment of growth, development, and adverse-event patterns. The study contributes descriptive information for a rare pediatric population, while the uncertainty and incomplete reporting define important limits on what can be concluded.

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 estimates come from small groups: 7 participants in the PPL group and 5 in the BBS group. The broad 95% confidence intervals reflect limited precision, and the estimates may not represent response proportions in other children with these conditions. The registry reports the study enrollment as 12 but does not provide further detail about participant flow or reasons for any difference between enrollment and the group-specific primary analysis counts.

The study is open-label, and no placebo or untreated comparator is described among the posted arms. Consequently, the primary response proportions cannot separate changes observed during the study from changes that might have occurred without the intervention. Although allocation is classified as randomized, the randomization process and its relation to the PPL and BBS groups are not reported in the registry record.

The endpoint is based on crossing a threshold in BMI Z-score. It does not communicate the size or distribution of individual changes, and the posted primary results do not include a mean change estimate. The registry lists several secondary outcomes, but their numerical findings are not reported alongside the primary response results.

Details needed to evaluate analysis choices are also absent. The confidence interval method, missing-data handling, multiplicity approach, prespecified statistical procedures, and sample-size justification are not reported in the registry record. The available intervention descriptions are incomplete, and the record does not give full details about adherence, treatment exposure, or dose changes. Safety counts are descriptive and arise from small groups, with no reported comparator for context.

These limitations do not invalidate the reported observations, but they constrain their precision, causal interpretation, and generalizability. The results are best read as group-specific findings from this completed study rather than as a definitive comparative estimate.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity — NCT04966741.
• Registry record last updated 2024-11-27; status last verified 2024-11.
• Results first posted 2024-07-10.
• 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 NCT04966741, a completed phase 3, multicenter, 1-year, open-label study of setmelanotide in children aged 2 to <6 years with rare genetic causes of obesity. It lists randomized allocation, no masking, a parallel model, and an enrollment of 12. The recorded study start date is 2022-03-08 and the primary completion date is 2023-09-18.

The primary endpoint is the percentage with a BMI Z-score decrease of at least 0.2 from baseline to Week 52. The PPL group result is 85.7% with a 95% confidence interval of 54.1% to 100.0%; the BBS group result is 80.0% with a 95% confidence interval of 28.4% to 99.5%. The registry lists 7 secondary outcomes, but numerical secondary results are not reported with these primary results. Serious adverse events and deaths are recorded as 0 in each group; other treatment-emergent adverse events are recorded for all participants in each group.