Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway (NCT05194124), a randomized phase 3 study. The primary outcome is Maximum Drug Concentration (Cmax) of Setmelanotide After QD Administration in the Run-in Period.

2. Clinical Question

3. Trial Design

NCT05194124 is a Phase 3 randomized, triple-masked crossover trial sponsored by Rhythm Pharmaceuticals, Inc. It enrolled 19 participants and is recorded as completed. The study start date was 2021-12-21, and the primary completion date was 2023-10-19. The trial concerns participants with specific gene defects in the melanocortin-4 receptor pathway, including the listed conditions Bardet-Biedl Syndrome and POMC Deficiency.

The official title describes a comparison of daily and weekly setmelanotide, followed by a crossover to open-label once-weekly setmelanotide. The run-in period used once-daily setmelanotide at 2 mg, 2.5 mg, or 3 mg for 1 week. In the double-blind period, participants entering on 2 mg or 2.5 mg daily received 20 mg or 25 mg weekly, respectively, with matching daily placebo. Participants entering on 3 mg daily could receive 3 mg daily with matching weekly placebo or 30 mg weekly with matching daily placebo. These double-blind treatments lasted 13 weeks.

The open-label period used weekly treatment for 13 weeks. The registry describes weekly doses of 20 mg, 25 mg, or 30 mg according to the participant's prior treatment group. The record's open-label description for the 30 mg group also refers to participants who had received 3 mg daily or 30 mg weekly in the double-blind period.

The primary outcome is a pharmacokinetic measure from the run-in period, not a clinical outcome measuring symptoms or disease status. Although the design includes a crossover and a daily-versus-weekly comparison, the posted primary outcome data are group summaries for once-daily dosing. The record does not report a completed statistical comparison between formulations for this endpoint.

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 20 participants were screened and 19 were randomized and treated in this study. The study consisted of a run-in period of up to 1 week in which the participants received once daily (QD) setmelanotide \[2 milligrams (mg), 2.5 mg, or 3 mg\]; a 13-week double-blind period in which the participants were randomized to either QD or once weekly (QW) setmelanotide; and a 13-week non-randomized open-label period where all participants received open label QW setmelanotide.

Only the first 6 of 10 groups are shown.

Run-in Period (1 Week)

Double Blind (DB) Period (13 Weeks)

Reasons for not completing this period:

Open Label (OL) Period (13 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in the Pharmacokinetic Analysis Set (PKAS) (all participants who received at least 1 dose of setmelanotide and who had a sufficient number of measurable plasma concentrations to permit assessment of noncompartmental parameters) with available data were analyzed.

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: Full Analysis Set (FAS) included all participants who received at least 1 dose of setmelanotide after the randomization.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Drug Concentration (Cmax) of Setmelanotide After QD Administration in the Run-in Period, measured over Pre-dose (0 hour) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose at Week -1.

The primary endpoint is maximum drug concentration, or Cmax, of setmelanotide after once-daily administration during the run-in period. It is expressed in nanograms per milliliter (ng/mL) and summarized as a mean with standard deviation where reported. The registry says Cmax was determined directly from individual concentration-time data. Concentrations were assessed pre-dose and at specified postdose times at Week -1.

As a general pharmacokinetic concept, Cmax describes the peak concentration observed after a dose. It is used to characterize one aspect of drug exposure and can help describe how concentration changes over time after administration. It does not, on its own, measure clinical benefit, establish a preferred dosing schedule, or describe the full concentration-time profile. Interpretation depends on the sampling schedule, the underlying individual measurements, and the analysis population.

The posted endpoint pertains to daily dosing in the run-in period. It therefore provides descriptive concentration summaries for the daily-dose groups, rather than a direct endpoint result for the randomized weekly-versus-daily comparison. The registry record does not report a treatment contrast, confidence interval, or inferential test for these Cmax summaries.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant's Cmax is a measured concentration, and the posted group summaries use means. The registry also reports standard deviations where available. These are descriptive statistics. They condense individual measurements into a central value and a measure of spread, but they do not by themselves test whether treatment groups differ.

What does the mean describe?

As a general statistical concept, the arithmetic mean is the sum of measured values divided by the number of observations. It is commonly used to summarize continuous outcomes, especially when the mean itself is clinically or scientifically interpretable. A mean can be affected by unusually high or low observations, so it is useful to consider it alongside a measure of variability and the underlying data distribution. The registry describes the primary parameter as a mean and gives the concentration unit as ng/mL.

For this endpoint, the mean Cmax values are 29.4, 44.8, and 59.9 ng/mL for the 2 mg, 2.5 mg, and 3 mg daily groups, respectively. These are summaries of the recorded concentration data, not estimates adjusted for other characteristics. No adjusted analysis is reported in the registry record.

How should the standard deviation be read?

As a general statistical concept, the standard deviation describes the spread of observations around their mean on the outcome's measurement scale. A larger standard deviation indicates greater observed variation among individual values. The reported standard deviations are 3.49 for the 2 mg group and 29.6 for the 3 mg group. No standard deviation is reported for the 2.5 mg group. With only 1.0 participant represented in that group, a within-group spread cannot be estimated from the posted group summary.

Dispersion matters because the same mean can arise from tightly clustered or widely dispersed observations. For pharmacokinetic data, variation among participants can be important when describing exposure. The posted group summaries do not show individual values or a distributional plot in the registry record, so they do not reveal the shape of the concentration data or whether unusual observations influence a group mean.

What would a treatment comparison require?

A comparison between daily and weekly dosing would require an analysis that defines the contrast and accounts for the trial design and the data structure. In a crossover trial, observations from the same participant under different treatment periods are related rather than independent. As a general statistical principle, an analysis should account for that within-participant relationship and should define how period and sequence are handled when relevant. The registry record does not report the planned model, the treatment contrast, or the handling of period or sequence effects for the primary endpoint. Those details cannot be inferred from the fact that the study is a crossover trial.

The record reports that the primary outcome uses the Pharmacokinetic Analysis Set, defined as participants who received at least 1 dose and had enough measurable plasma concentrations to assess noncompartmental parameters, with available data analyzed. This identifies the intended analysis population in broad terms. It does not state how many participants contributed to each primary summary beyond the posted group sizes, nor does it describe how missing concentration measurements were handled.

The registry indicates that values were missing or not estimable for a two-arm comparison of this continuous endpoint. No two-arm effect estimate, standard error, confidence interval, or test statistic is posted. Without a defined contrast and its uncertainty, the differences between the displayed group means should not be treated as a formal estimate of a treatment effect. No recalculated comparison is presented, so there is no sponsor-versus-recalculation discrepancy to resolve.

What do uncertainty estimates add?

As a general explanation, a confidence interval expresses a range of values compatible with the data under a specified statistical method. Its width reflects both the observed variability and the amount of information available. A narrow interval suggests more precision than a wide interval, while an interval that is absent provides no direct visual or numerical estimate of uncertainty. The registry record does not post confidence intervals for the Cmax means or for a comparison.

The group sizes are small, especially for the 2 mg and 2.5 mg groups. Small groups generally produce less stable estimates of a mean and its variability. The reported standard deviations and means remain useful as summaries of what was observed, but they should not be read as precise estimates of the broader population's pharmacokinetic distribution.

The registry record lists 15 outcome measures and 3 posted secondary outcomes, including treatment-emergent adverse events and injection site reactions over stated periods. It reports 0 analyses. It does not report a statistical analysis plan or explain how multiple outcomes or repeated analyses were to be handled. General statistical practice treats multiplicity as relevant when several hypotheses are tested, because repeated testing can increase the chance of a false-positive finding. Since no inferential tests are posted for the primary endpoint, the record does not support an assessment of multiplicity adjustment for it.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 15 outcome measures, of which 3 secondary outcomes are posted: participants with treatment-emergent adverse events, participants with injection site reactions from baseline through Week 13, and participants with injection site reactions from Week 14 through Week 27. The record reports 0 analyses. It does not report a statistical analysis plan, a hierarchy for testing outcomes, or a multiplicity adjustment. Therefore, the intended control of false-positive findings across outcomes is not reported in the registry record.

For the primary pharmacokinetic endpoint, the analysis population is described as the Pharmacokinetic Analysis Set: participants who received at least 1 dose and had a sufficient number of measurable plasma concentrations to assess noncompartmental parameters, with available data analyzed. The posted group sizes for the daily-dose summaries are 2.0, 1.0, and 16.0. These figures describe the posted summaries; the record does not provide a fuller accounting of screening, treatment-period, or outcome-specific missingness.

Although the endpoint description notes that the analysis used available data, the registry record does not explain how missing measurements were handled, whether missingness was assessed, or whether any sensitivity analyses were performed. It also does not report a reason for unavailable data or a method for imputing values. The analysis population definition helps clarify which participants could contribute, but it does not establish that missing data were absent or that their impact was negligible.

For the treatment comparison, the registry reports that a two-arm comparison of this continuous endpoint was not estimable because values were missing or not estimable. The registry record does not report the planned statistical model, the handling of the crossover structure, or an inferential analysis for that contrast. Consequently, neither multiplicity control nor the robustness of a comparative result can be evaluated from the posted primary outcome record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry safety records list serious adverse events, other adverse events, and deaths by treatment period and group. The serious adverse event count is 0 in every listed group, and the death count is 0 in every listed group. These are group-level records for the listed periods; they do not establish that no events occurred outside the recorded groups or timeframes.

Other adverse events are recorded as follows: during run-in, the counts were 0 in the 2 mg group, 0 in the 2.5 mg group, and 1 in the 3 mg group. During the double-blind period, the counts were 2 for 20 mg weekly, 1 for 25 mg weekly, 9 for 3 mg daily, and 6 for 30 mg weekly. During the open-label period, the counts were 0 for 20 mg weekly, 1 for 25 mg weekly, and 10 for 30 mg weekly. The corresponding at-risk group counts are recorded separately for each period.

These are counts, not comparative risk estimates. The registry record does not provide a statistical comparison of safety between formulations, and the groups are small. The entries do not identify specific event types here, so the counts should not be interpreted as describing severity beyond the separate serious-event category or as explaining clinical importance.

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

The primary result describes peak setmelanotide concentration after once-daily administration during the run-in period. The posted means are 29.4 ng/mL for 2 mg, 44.8 ng/mL for 2.5 mg, and 59.9 ng/mL for 3 mg. These values answer a descriptive pharmacokinetic question about the recorded daily-dose data. They do not, on their own, estimate the effect of switching from daily to weekly dosing.

The distinction between description and comparison is central. A set of group means can show the observed summaries, but a treatment comparison requires an estimate of the contrast, an appropriate analysis of the trial design, and a measure of uncertainty. The registry record does not post those elements for the primary endpoint. It also notes that values were missing or not estimable for a two-arm comparison of this continuous outcome. No conclusion about the size or precision of a daily-versus-weekly difference can be drawn from the primary results as posted.

The result also does not establish how Cmax relates to clinical outcomes for the participants in this trial. Cmax is a measure of peak concentration, not a direct measure of symptoms, disease course, or patient experience. The posted primary endpoint does not answer whether one formulation is more effective, more acceptable, or safer than another.

The numbers are especially limited by the small group sizes for the 2 mg and 2.5 mg summaries and the absence of a standard deviation for the 2.5 mg group. The 3 mg group has a larger posted group size and a reported standard deviation, but that descriptive information still does not replace an inferential comparison. The record does not provide confidence intervals that would show uncertainty around the means.

The safety entries are also descriptive. They report zero serious adverse events and zero deaths in each listed group, alongside varying counts of other adverse events. They do not provide a formal comparative safety analysis. Overall, the record documents a completed crossover study and posts selected pharmacokinetic and safety summaries, while leaving the primary formulation comparison and its precision unreported.

13. Why This Trial Matters Statistically

This trial is statistically notable because its design and its posted primary endpoint address different questions. The randomized crossover design is intended to compare daily and weekly formulations, while the primary outcome reported in the registry is Cmax after daily dosing in the run-in period. That distinction matters: a study can include a comparative design without the registry record posting a comparative estimate for every outcome.

The record also illustrates why analysis populations and group sizes matter when interpreting pharmacokinetic summaries. The primary analysis is restricted to participants with dosing and sufficient measurable plasma concentrations, and the posted daily-dose groups are small for the 2 mg and 2.5 mg doses. Group means can be reported in such circumstances, but their precision and representativeness are difficult to judge without individual data or uncertainty intervals.

Another statistical issue is the crossover structure. Repeated observations from the same participant are generally correlated, so an analysis of a crossover comparison needs to reflect that relationship. The registry record does not report the model or the inferential comparison for the primary endpoint. Readers therefore cannot verify from the posted results how the study's design was incorporated into an analysis of formulation differences.

The record's reporting is useful in showing which pharmacokinetic summaries and safety counts were posted. At the same time, the absence of an estimable two-arm comparison, inferential statistics, and confidence intervals limits what can be concluded about relative exposure. The trial matters statistically as an example of why endpoint definition, analysis population, design-aware methods, and transparent reporting of uncertainty are all necessary for interpreting a comparison.

14. Limitations

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

The primary endpoint is a pharmacokinetic measure from the run-in period, whereas the trial's stated purpose includes a comparison of daily and weekly formulations. The posted Cmax results are grouped by daily dose and do not provide a direct estimate of the formulation contrast. The registry record specifically indicates that a two-arm comparison of the continuous endpoint was not estimable because values were missing or not estimable.

Group sizes are limited for the lower daily doses: the 2 mg group has 2.0 participants and the 2.5 mg group has 1.0 participant. The 2.5 mg group has no reported standard deviation. Although the 3 mg group has 16.0 participants and a reported standard deviation, these summaries do not show the underlying individual concentration data. Confidence intervals and inferential tests are not posted.

The endpoint is based on concentration sampling at stated timepoints at Week -1. The registry description says Cmax was determined directly from individual concentration-time data, but the record does not describe the detailed estimation procedures beyond that statement. It does not report the statistical model for any treatment comparison, how the crossover was handled, or how missing concentration values were addressed.

The safety records are organized by treatment period and group, and should be interpreted as period-specific counts. They do not provide comparative estimates or event details in the posted summary. The record also does not report a multiplicity strategy or a statistical analysis plan. These limitations leave the descriptive summaries informative about the recorded data but insufficient for evaluating the precision or robustness of a comparative treatment effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway — NCT05194124.
• Registry record last updated 2024-11-26; status last verified 2024-11.
• Results first posted 2024-11-26.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT05194124 is a completed Phase 3 randomized, triple-masked crossover trial sponsored by Rhythm Pharmaceuticals, Inc. It enrolled 19 participants with specific gene defects in the melanocortin-4 receptor pathway, including Bardet-Biedl Syndrome and POMC Deficiency. The trial start date was 2021-12-21, and the primary completion date was 2023-10-19.

The primary outcome was mean Cmax of setmelanotide after once-daily dosing in the run-in period, measured in ng/mL. Posted means were 29.4 for 2 mg, 44.8 for 2.5 mg, and 59.9 for 3 mg; standard deviations were 3.49 and 29.6 for the 2 mg and 3 mg groups, respectively. The record reports no estimable two-arm comparison for this continuous endpoint and lists 0 analyses.

Serious adverse event counts and deaths were 0 in each reported group. Other adverse-event counts are recorded by treatment period. The registry record does not report inferential comparisons or confidence intervals for the primary endpoint.