DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway (NCT04963231), a randomized phase 2 study. The primary outcome is Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1.

2. Clinical Question

3. Trial Design

DAYBREAK is identified as a Phase 2 trial of setmelanotide in people with specific gene variants in the MC4R pathway. It is described as a two-stage study: open-label treatment followed by a randomized, double-blind, placebo-controlled stage. The registry lists a parallel-group model and triple masking, while the stage descriptions characterize Stage 1 as open-label and Stage 2 as double-blind. Which trial roles were masked under the overall triple-masking designation is not reported in the registry record.

The registry records enrollment of 164 participants. Stage 1 assigned participants to once-daily subcutaneous setmelanotide from Day 1 to Week 16. For participants ≥12 years of age, the described regimen began at 2.0 mg once daily for approximately 2 weeks, followed by 3.0 mg once daily. The age-specific dosing description for participants younger than 12 is incomplete in the registry record, so no further detail can be given.

Participants from Stage 1 who were eligible for Stage 2 received either setmelanotide 3.0 mg or matching placebo 3.0 mg once daily from Week 16 to Week 40. The serious-adverse-event record lists 35 participants at risk in the Stage 2 setmelanotide group and 14 in the Stage 2 placebo group. Eligibility rules, the number screened for Stage 2, and the reasons some participants did not enter Stage 2 are not reported in the registry record.

The recorded start date is 2021-11-30, the primary completion date is 2023-08-04, and the study status is completed. These dates describe the registry record; they do not provide details about follow-up beyond the stated treatment stages or about the timing of analysis.

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 218 participants were screened and 164 participants received at least one dose of trial medication in Stage 1.

Stage 1 (Open-Label, Duration: 16 Weeks)

Reasons for not completing this period:

Stage 2 (Double-Blind, Duration:24 Week)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in the Safety Analysis Set 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: Safety Analysis Set included all participants who received at least one dose of trial medication.

6. Primary Endpoint

The registry lists the primary outcome as Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1, measured over Baseline to Week 16.

The primary outcome is a count of participants by genotype who demonstrated a significant, clinically meaningful response at the end of Stage 1. The registry defines response as achieving a ≥5% reduction in BMI from baseline. BMI is calculated from weight and height, with baseline defined as the last available measurement before Stage 1 treatment began. The stated timeframe is baseline to Week 16.

This is a binary, threshold-based outcome: each participant either meets the stated response definition or does not. Reporting the count can communicate how many participants crossed the prespecified BMI-change threshold, while genotype-specific reporting can describe the outcome across the listed genetic groups. Such a threshold makes a continuous measure easier to classify for a response summary, but it does not show the full distribution of BMI changes. Participants just below and just above the threshold are placed in different categories even if their actual changes are similar.

The registry says participants in the Safety Analysis Set with available data were analyzed. It does not report the response counts, genotype-specific denominators, or an effect estimate for this primary outcome. Consequently, the endpoint definition is available, but the posted record does not support an assessment of how many participants met the threshold or how precisely that proportion was estimated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary response outcome represent?

In general, a binary endpoint classifies each participant into one of two categories, such as meeting or not meeting a stated response definition. The DAYBREAK primary endpoint uses a threshold: a participant is a responder if BMI has fallen by ≥5% from baseline by Week 16. The registry’s stated measure is a count of responders, with reporting by genotype. A count alone is difficult to interpret without the number of participants assessed in each group; those denominators and the primary outcome counts are not reported in the registry record.

Threshold outcomes can be straightforward to communicate, but they compress information. They do not show the size of a BMI change among participants who meet the threshold, nor the pattern of changes among those who do not. The registry also lists secondary outcomes concerning mean and percent change in BMI, body weight, BMI Z-score, and hunger score for specified age groups and genotypes. The numerical results for those outcomes are not reported in the information available in the registry record.

What can a treatment comparison establish?

In general, randomized comparisons estimate differences between groups formed by allocation to different treatments. A placebo-controlled, double-blind comparison can help distinguish a treatment contrast from changes that might also occur without the active treatment, subject to the trial design and analysis. In DAYBREAK, however, the primary endpoint is specifically for Stage 1, which is described as open-label setmelanotide treatment. Its response count is therefore not a randomized setmelanotide-versus-placebo estimate.

The trial’s overall description includes a randomized, double-blind, placebo-controlled Stage 2, and the Stage 2 descriptions specify setmelanotide and matching placebo. But the registry record does not report numerical efficacy results or an analysis comparing those groups. It also does not state the randomization method, stratification factors, or analysis model. Those details should not be inferred from the presence of a randomized design label alone.

How should uncertainty be assessed?

In general, a point estimate describes the result observed in a sample, while a confidence interval conveys uncertainty around that estimate under the chosen statistical model. Wider intervals indicate less precision, and narrower intervals indicate greater precision, all else being equal. For a binary endpoint, uncertainty depends on both the number of participants and the number meeting the response definition. The registry does not report the primary outcome counts, denominators, confidence intervals, or a statistical test, so the precision of the primary result cannot be evaluated.

Statistical significance and clinical interpretation are distinct concepts. A significance test addresses compatibility with a specified null hypothesis under its assumptions; it does not by itself establish the size or practical importance of an effect. In this trial, the outcome definition calls a ≥5% BMI reduction clinically meaningful, but the registry record does not report the results needed to assess how often that criterion was met or whether any between-group estimate was statistically evaluated.

What do the sample-size assumptions mean?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to be detected, variability, allocation, significance level, and desired power. The registry’s planning description says the illustration uses the observed effect, two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It also states that the effect to detect is a specified fraction of the observed effect. These are planning assumptions, not a description of the trial’s actual design rationale. The sample-size justification for DAYBREAK is not reported in the registry record.

Planning illustrations should not be interpreted as observed power. Observed power is not a substitute for an effect estimate and its uncertainty after the study is complete. The record does not report numerical sample-size illustrations in the information used for this explanation, so no planning count can be interpreted. Any planning estimate should be understood as conditional on its assumptions, rather than as a statement of what the trial observed.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability is greater than the variability assumed by a statistical model. It can make model-based standard errors too small if the analysis does not account for the extra variation, which can in turn make confidence intervals too narrow. This concept can matter for outcomes analyzed with count or rate models. The registry does not report a model for the primary endpoint or indicate whether over-dispersion was assessed; no claim about its presence or handling can be made for this trial.

What does the analysis population tell us?

The primary outcome description states that participants in the Safety Analysis Set with available data were analyzed. An analysis population defines which participants contribute to an estimate, and its precise meaning depends on the protocol and analysis plan. The record does not provide the operational definition of this set, the number with available endpoint data, or details of how missing measurements were handled. Accordingly, the analysis population cannot be equated with all 164 enrolled participants without further information.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures and 0 analyses. The primary endpoint is one of these measures, with secondary outcomes covering BMI, body weight, BMI Z-score, and hunger score across specified age groups and genotypes. Multiple outcomes and subgroup summaries can create multiplicity: when many hypotheses are considered, the chance of at least one apparently unusual result can increase. In general, an analysis plan may address this by prespecifying a primary comparison, ordering tests, or adjusting inference. The multiplicity strategy for this trial is not reported in the registry record.

The primary outcome population is described as the Safety Analysis Set with available data. The registry does not state how missing BMI or height measurements were handled, whether participants with missing Week 16 data were excluded, or whether any imputation or sensitivity analysis was used. The number of participants with available primary-outcome data is also not reported. These omissions matter because the outcome is defined by change from baseline, which requires usable measurements at the relevant time points.

The record also does not report the statistical analysis plan, the model used for genotype-specific results, or whether subgroup analyses were prespecified. It is therefore not possible to determine how uncertainty, multiplicity, or missing data were addressed in the sponsor’s analysis. These are not details that can be reconstructed from the outcome labels alone.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: depression (1.2%), gastritis (0.6%), vomiting (0.6%), headache (0.6%), asthma (0.6%).

The serious-adverse-event listings report 6 affected participants among 164 at risk during Stage 1 setmelanotide treatment. In Stage 2, the listing reports 0 among 35 at risk for setmelanotide and 0 among 14 at risk for placebo. Deaths are listed as 0 in all three groups. These are counts for the specified groups and stages; they should not be read as a complete safety comparison or as evidence that an event cannot occur.

The groups differ in size and in how participants entered each stage. Stage 1 was open-label. Stage 2 included participants from Stage 1 who were eligible to continue and was described as double-blind. The record does not report eligibility criteria or a formal comparison of serious-event rates. It also lists other adverse events affecting 160 of 164 participants in Stage 1, 25 of 35 in Stage 2 setmelanotide, and 10 of 14 in Stage 2 placebo.

The listed serious terms include Depression at 1.2%, and Gastritis, Vomiting, Headache, Asthma, and Angioedema at 0.6% each. The registry record does not give enough context in these listings to establish causal attribution. Counts and terms describe reported events; they do not by themselves determine whether treatment caused an event or support a comparative safety conclusion.

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

The registry record defines a clinically meaningful Stage 1 response as a ≥5% reduction in BMI from baseline by Week 16. It identifies the population, timeframe, and general outcome measure, and describes once-daily open-label setmelanotide treatment during that stage. It also describes a later double-blind stage with setmelanotide and placebo for participants eligible to continue.

What the record does not provide is the numerical primary outcome result. There are no reported responder counts, denominators by genotype, or estimates of uncertainty in the outcome description. Thus, the posted information does not establish how many participants met the threshold, how consistently the response appeared across genotypes, or how precisely any response rate was estimated. A numerical outcome conclusion cannot be drawn from the endpoint definition alone.

The Stage 1 outcome also should not be confused with a randomized treatment effect. Because Stage 1 was open-label and the stated primary measure is a response count during that stage, it does not directly compare setmelanotide with placebo. Stage 2 includes a placebo group, but the registry record does not report efficacy estimates from that comparison. Its participants were selected from those eligible after Stage 1, so Stage 2 represents a different population and design context.

The adverse-event counts offer descriptive safety information, not a verdict about cause or comparative risk. The Stage 2 groups have different numbers at risk, and the record does not report a formal safety analysis. A zero count in a group means that no affected participants are listed for that group in this record; it does not establish that the underlying risk is zero.

More broadly, an endpoint definition, trial design description, and adverse-event listing are not substitutes for posted outcome analyses. The absent numerical primary results, uncertainty estimates, missing-data methods, and analysis plan limit what can be concluded from the registry entry. These limitations concern what the record reports and do not determine what analyses may exist elsewhere.

13. Why This Trial Matters Statistically

DAYBREAK illustrates why a trial’s design and outcome definition need to be read together. Its primary outcome is a threshold-based response count during an open-label stage, while its overall design also includes a later randomized, double-blind, placebo-controlled stage. Those stages answer different kinds of questions: an open-label response count describes outcomes under treatment, whereas a randomized comparison is designed to estimate a contrast between assigned groups.

The genotype-specific framing is also statistically important. The primary outcome is intended to be presented overall and by specified primary gene, and the secondary outcomes include several measures and age-defined groups. Subgroup summaries can help describe variation across participant characteristics, but they may be based on fewer observations and require careful attention to uncertainty and multiplicity. The registry record does not provide the subgroup counts or the analysis plan needed to assess these issues.

The record also shows why endpoint reporting must include results, denominators, and uncertainty—not only a definition. Without the primary response counts or estimates, readers cannot assess the size or precision of the result. Likewise, the serious-adverse-event counts should be interpreted in light of stage, treatment group, and the numbers at risk, rather than combined into a single trial-wide comparison.

Finally, registration details and outcome reporting serve distinct purposes. The registry describes the trial’s phases, interventions, outcome definitions, and some safety counts, yet it does not report numerical efficacy results or key analysis details. Recognizing that boundary is central to a sound statistical reading: design labels indicate how a study was intended to operate, while conclusions depend on reported analyses and their uncertainty.

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 most consequential limitation for interpreting the primary endpoint is that its numerical results are not reported in the registry record. The endpoint definition is specific, but no counts, denominators, genotype-level estimates, confidence intervals, or significance tests are included. The entry therefore does not permit an assessment of response magnitude or precision.

The primary outcome is measured in an open-label stage without a concurrent placebo group. This design description means the primary response count is not itself a randomized comparison. Although the trial includes a later placebo-controlled stage, the registry does not report an efficacy comparison from that stage. Stage 2 participants were eligible continuations from Stage 1, and the criteria governing entry are not reported.

Further limitations arise from missing methodological detail. The registry does not report the statistical analysis plan, sample-size justification, handling of missing endpoint data, multiplicity approach, or definitions of the genotype subgroups. It also does not provide the number of participants with available primary-outcome data. The statement that the Safety Analysis Set with available data was analyzed does not resolve these questions.

The overall masking designation is triple, while the stage descriptions specify open-label Stage 1 and double-blind Stage 2. The roles masked under the overall designation are not stated. The Stage 1 age-specific dosing description for participants younger than 12 is incomplete in the record. Finally, serious-adverse-event counts are descriptive and come from groups with different numbers at risk and different stage-selection histories. The registry does not provide a formal comparative safety analysis or establish causal attribution for the listed events.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway — NCT04963231.
• Registry record last updated 2025-07-02; status last verified 2025-07.
• Results first posted 2024-10-24.
• 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

DAYBREAK is a completed Phase 2 trial of setmelanotide in participants with obesity and specific MC4R-pathway gene variants. The registry describes open-label Stage 1 treatment from Day 1 to Week 16, followed by a randomized, double-blind, placebo-controlled Stage 2 from Week 16 to Week 40 for eligible participants. Enrollment is listed as 164.

The primary outcome counts participants by genotype who achieved a ≥5% reduction in BMI from baseline by the end of Stage 1. Numerical primary-outcome results and analyses are not reported in the registry record. Serious-adverse-event counts are listed by stage and treatment group, but the record does not report a formal comparative safety analysis.