Efficacy And Safety Evaluation of Glepaglutide in Treatment of Short Bowel Syndrome (SBS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy And Safety Evaluation of Glepaglutide in Treatment of Short Bowel Syndrome (SBS) (NCT03690206), a randomized phase 3 study. The primary outcome is Change in Weekly Parenteral Support (PS) Volume.

2. Clinical Question

The clinical question is framed around the amount of parenteral support received each week. The endpoint uses a continuous volume measure, rather than only recording whether support was reduced or stopped. This allows the primary analysis to represent changes across the range of recorded weekly volumes. The trial also recorded secondary outcomes related to clinical response in parenteral support volume, days off support, and being weaned off support, among other measures. These outcomes address related but distinct aspects of parenteral support. They do not replace the prespecified primary question, and their results need to be read with attention to their definitions and statistical uncertainty.

3. Trial Design

NCT03690206 is a completed phase 3 randomized trial of glepaglutide for short bowel syndrome. The official title describes an international, multicenter, randomized, double-blind, placebo-controlled design. The registry record characterizes masking as quadruple and the trial model as parallel. It reports enrollment of 106 participants and a primary completion date of 2022-07-26. The sponsor is Zealand Pharma.

Participants were assigned to one of three injection schedules: glepaglutide subcutaneously twice weekly, glepaglutide subcutaneously once weekly with placebo once weekly, or placebo subcutaneously twice weekly. For the primary outcome, the reported arm sizes were 35, 35, and 36, respectively. The primary efficacy analyses used the Full Analysis Set, defined as randomized patients who received at least one dose of trial drug. Patients were analyzed according to their randomized group.

The primary endpoint was change in weekly parenteral support volume from baseline to Week 24. Baseline volume was derived from a valid 7-day period before visit 1, during the stabilization phase. Weekly values at later visits were based on the valid 7-day period before each visit and came from volumes recorded by patients in an electronic diary. The primary outcome timeframe was 24 weeks.

The registry record lists secondary outcomes concerning response in parenteral support volume, days off support, weaning, energy content, days on support, weekly volume change, and patient global impression of change. It reports 14 outcome measures and 8 analyses in the posted results, while the record identifies 13 secondary outcomes as posted. Additional detail on the full protocol, eligibility criteria, treatment adherence, and the statistical analysis plan is not reported in the registry record.

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: Patients were diagnosed with SBS and required PS at least 3 days/week. They were willing to adhere to an individual pre-defined drinking menu during 48 h measurement periods and maintain a stable weight. The drinking menu and the PS volume and content were adjusted during an optimization phase following by a stabilization phase.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) consisted of all randomized patients who received at least one dose of trial drug (glepaglutide or placebo). All efficacy analyses were based on the FAS. Patients were included in the analyses as randomized.

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.

6. Primary Endpoint

The registry lists the primary outcome as Change in Weekly Parenteral Support (PS) Volume, measured over 24 weeks.

The primary endpoint measures change in weekly parenteral support volume, expressed in L/week, from baseline to Week 24. Parenteral support is the volume-based treatment measure at the center of the trial’s stated primary objective: evaluating whether glepaglutide reduces the volume required by patients with short bowel syndrome. A continuous volume measure captures the amount of change, rather than reducing the result to a yes-or-no response category.

Baseline was defined using actual weekly volume derived from a valid 7-day period before visit 1, during the stabilization phase. At Weeks 1, 2, 4, 8, 12, 16, 20, and 24, actual weekly volume was derived from the valid 7-day period preceding the visit. Patient entries in an electronic diary were the source for the volume derivation. This repeated measurement structure allows the primary analysis to use observations collected during follow-up, although the specific way the mixed model handled those repeated observations is not reported in the registry record.

The reported arm estimates are least-squares means with 95% confidence intervals. A confidence interval conveys the uncertainty around an estimated mean change; it is not a range containing every participant’s change. Negative changes indicate lower recorded weekly volume relative to baseline under the endpoint’s direction of measurement. The primary comparison is the model-estimated difference from placebo, not simply a comparison of the arm estimates considered in isolation. The registry record does not report a patient-level threshold that defines a clinically meaningful change, so the size of an estimated volume change should not be treated as proof of a particular individual response.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: each participant’s outcome is a change in weekly volume, and the arm summaries are least-squares means. The registry reports a mixed models analysis for comparisons with placebo. A mixed model is a general statistical approach for outcomes measured repeatedly, which can account for the relationship among observations from the same participant. The registry record does not report the model’s covariates, covariance structure, estimation details, or missing-data assumptions, so those features cannot be evaluated from the posted description alone.

What does a confidence interval communicate?

General statistical explanation: a confidence interval expresses uncertainty around an estimate under the assumptions of the analysis. For the primary comparisons, the 95% intervals describe uncertainty in the estimated difference to placebo. An interval spanning zero is compatible with no difference as well as with effects in either direction covered by the interval. An interval entirely on one side of zero indicates that the values covered by that interval are on that side, but does not establish clinical importance. Clinical interpretation also depends on the size and meaning of the endpoint, which the registry does not define through a minimum clinically important difference.

The primary estimates are least-squares means rather than simple arithmetic averages identified as such in the record. In general, least-squares means are model-based estimates and can reflect adjustment or structure in the fitted analysis. The registry record does not specify which terms were included, so it is not possible to describe them as adjusted for particular baseline characteristics. The reported comparison is the model’s estimated difference from placebo, with its own confidence interval and p-value. It should be used for the stated comparison rather than inferred by subtracting the displayed arm estimates.

How should the binary outcomes be read?

The posted secondary outcomes include counts of participants meeting a response definition or reaching another binary outcome. A risk difference is the difference between the observed proportions in two groups, expressed on a probability scale. A confidence interval for a risk difference describes uncertainty in that difference. The simple recalculations accompanying the posted binary counts are unadjusted comparisons from summary data. They do not reproduce the sponsor’s Cochran-Mantel-Haenszel analyses, which are the analyses reported by the registry for the corresponding comparisons.

General statistical explanation: binary outcomes can be especially imprecise when event counts are small. When no participants in a group experience an event, some relative measures may be undefined or unstable without a specified correction or model. That is why estimates and confidence intervals should be interpreted in light of the counts, rather than as precise measurements of a durable difference. The registry reports a zero count for one group on the weaning outcome; no recalculated relative risk or odds ratio is listed for that comparison.

Why can over-dispersion matter?

General statistical explanation: over-dispersion occurs when observed variability is greater than a model’s assumptions allow. If it is ignored, uncertainty estimates may be too small and tests may appear more decisive than warranted. This concept is relevant to some count or rate models, but the registry record does not identify an over-dispersion analysis for the posted primary continuous endpoint or secondary binary outcomes. It would therefore be inappropriate to infer that the trial did or did not assess it.

For planning, sample-size illustrations based on observed binary effects are not evidence of the trial’s achieved power. They describe hypothetical future participant requirements under stated assumptions, including a two-sided significance level of 0.05, equal allocation between the compared arms, and a normal approximation. The illustrations use fractions of the observed effect as planning targets. Such calculations are sensitive to the effect chosen: planning for a smaller effect generally requires more participants than planning for the full observed effect. The registry does not report that these illustrations were the trial’s design justification. The actual sample-size justification is not reported in the registry record.

General statistical explanation: a p-value measures how compatible the observed data are with a specified null model, under the analysis assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical relevance of an effect. The confidence interval and estimated difference therefore matter alongside the p-value. In this trial, the primary comparisons are reported using the sponsor’s mixed-model analysis, while secondary binary outcomes include sponsor-reported Cochran-Mantel-Haenszel analyses and simple unadjusted recalculations. Because these methods answer related but not identical statistical questions, their estimates should not be treated as interchangeable.

10. Analyses Reported by the Sponsor

The primary results are reported as mixed-model comparisons to placebo. The twice-weekly glepaglutide comparison has an estimated difference of -2.28 L/week, with a 95% confidence interval from -3.83 to -0.73 and a p-value of 0.004. The once-weekly glepaglutide schedule has an estimated difference of -0.91 L/week, with a 95% confidence interval from -2.52 to 0.71 and a p-value of 0.270. These are the sponsor’s reported analyses in the registry record and are the relevant results for the primary endpoint.

For binary secondary outcomes, the registry also reports Cochran-Mantel-Haenszel comparisons. The separate recalculations use unadjusted comparisons based on posted group counts and are not substitutes for those sponsor analyses. Differences between an unadjusted recalculation and a reported analysis can arise because the methods may use different statistical structures or estimands; the registry does not give enough methodological detail to attribute any particular difference to a specific adjustment. Recalculated estimates are therefore useful as a transparent check on summary counts, not as replacements for the analysis specified by the sponsor.

No discrepancy is identified between a recalculation and the sponsor analysis in the record. The sponsor’s reported analyses remain the primary basis for describing the trial’s formal comparisons. The registry record does not provide enough detail to reconstruct the full primary model or to verify every analytical choice independently.

11. Multiplicity, Missing Data and Analysis Populations

The registry record describes the Full Analysis Set as all randomized patients who received at least one dose of glepaglutide or placebo. It states that all efficacy analyses were based on this set and that patients were included as randomized. This definition does not include randomized patients who received no dose. The record does not report how many, if any, randomized patients were excluded for that reason.

For the primary outcome, the record specifies that baseline and follow-up values came from valid 7-day periods and that the source was patient electronic diary entries. The primary analysis is described as a mixed model. The record does not state how missing diary periods were handled, whether any imputation was used, what assumptions were made about missingness, or how sensitivity analyses addressed missing data. It also does not report the number of missing observations at each visit. These omissions limit assessment of whether incomplete follow-up could have affected the estimates.

The record lists numerous secondary outcomes and analyses, but does not report a family-wise error procedure, false-discovery procedure, gatekeeping strategy, or other multiplicity plan. It is also not reported in the registry record whether the primary and secondary outcome hierarchy was prespecified in a protocol or statistical analysis plan. Without that information, individual secondary p-values should not be interpreted as though they were protected from the risks of multiple testing.

Interim analyses, stopping rules, and any formal monitoring plan are not reported in the registry record. The sample-size justification is also not reported. The sample-size illustrations associated with observed secondary effects are planning exercises under stated assumptions, not evidence of observed power and not proof of the original design assumptions. The registry record does not establish that those illustrations were used to plan enrollment.

These limitations do not erase the reported estimates, but they define what can be concluded from the registry record. More detailed protocol and analysis-plan information would be needed to assess missing-data assumptions, multiplicity control, and the prespecified status of the analyses in depth.

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: stoma site haemorrhage (5.9%), pyrexia (5.7%), device related sepsis (5.7%), vascular device infection (5.7%), acetabulum fracture (2.9%).

The registry reports serious adverse events affecting 9 of 35 participants in the twice-weekly glepaglutide group, 10 of 35 in the once-weekly glepaglutide-plus-placebo group, and 7 of 36 in the placebo group. It reports no deaths in any of these groups. These counts describe participants with at least one serious adverse event as recorded in the registry; they do not state the total number of serious-event episodes or their duration.

The record also lists other adverse events affecting 30 of 35, 31 of 35, and 25 of 36 participants in the respective groups. The serious-event terms listed include stoma site haemorrhage at 5.9%, pyrexia at 5.7%, device related sepsis at 5.7%, vascular device infection at 5.7%, acetabulum fracture at 2.9%, and peripheral arterial occlusive disease at 2.9%. The registry excerpt does not provide the denominators or additional details needed to interpret these term-specific percentages fully.

These figures are descriptive and should not be treated as a complete comparative safety analysis. The registry record does not report event timing, severity beyond the serious classification, exposure-adjusted rates, or a statistical comparison for these counts. Differences in counts alone do not establish that an intervention caused an event or that the groups had equivalent safety. The figures describe what was posted for the trial and do not constitute medical advice.

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

The posted primary analysis estimates a more negative change in weekly parenteral support volume for the twice-weekly glepaglutide group than for placebo over the 24-week endpoint timeframe. Its estimated difference to placebo is -2.28 L/week, and the reported 95% confidence interval, from -3.83 to -0.73, lies below zero. For glepaglutide once weekly with placebo once weekly, the estimated difference is -0.91 L/week and its 95% confidence interval, from -2.52 to 0.71, includes zero. These are group-level model estimates and indicate different degrees of statistical precision for the reported comparisons.

The results do not show that every participant’s support volume changed in the same way. A group mean can coexist with substantial variation among individual participants, and the registry does not report the distribution of individual changes in the primary outcome. Nor does the record define a threshold that would establish a clinically meaningful change for an individual. Statistical evidence of a group difference and the clinical importance of that difference are related but separate questions.

The results also do not establish what would happen beyond the recorded trial timeframe, or how the estimates apply to people who would not have met the trial’s eligibility criteria. Further eligibility and population detail is not reported in the registry record. The primary analysis concerns a specific outcome, population, set of injection schedules, and follow-up period. It should not be generalized to other schedules or settings without supporting evidence.

Finally, the secondary outcomes and safety counts add descriptive context but do not remove uncertainty about missing data, multiplicity, or the full analysis plan. The registry record supports a careful account of its posted estimates, not a complete independent audit of the trial. It does not by itself establish a treatment recommendation or settle broader questions about benefits and harms.

14. Why This Trial Matters Statistically

This trial is statistically informative because it compares two glepaglutide schedules with placebo in a randomized, masked, parallel-group design and reports a continuous primary outcome tied to the stated objective. The primary measure records change in weekly parenteral support volume, while the mixed-model comparisons express each active schedule’s estimated difference from placebo. That distinction matters: arm-level changes describe what was estimated within each group, whereas the between-group contrast addresses the comparative question.

The reported primary estimates also illustrate why confidence intervals matter. The twice-weekly comparison’s interval is entirely below zero, while the once-weekly comparison’s interval includes zero. Those intervals communicate the precision and range of values compatible with each fitted analysis, rather than merely labeling results as positive or negative. The posted data therefore offer a more nuanced account than a single p-value or a comparison of arm means alone.

The trial also highlights a common interpretive challenge: secondary outcomes can support a fuller description but are numerous and use different measures. Their reported analyses should not be read as a set of independent replications of the primary endpoint, especially when a multiplicity plan is not reported. The registry’s binary outcomes make the size of event counts and the width of uncertainty intervals particularly relevant.

Finally, the registry record leaves important statistical details unavailable, including the primary model specification, missing-data handling, and multiplicity strategy. Those gaps do not make the posted estimates unusable, but they limit how fully readers can evaluate the assumptions behind them. The record is most useful when estimates, confidence intervals, analysis populations, and reporting limitations are considered together.

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 registry record gives only a brief description of the primary mixed-model analysis. It does not report the model terms, covariance structure, estimation method, diagnostic checks, or handling of missing observations. Although the endpoint definition specifies valid 7-day periods and an electronic diary source, the record does not say how an invalid or absent diary period affected inclusion in the analysis. This makes it difficult to assess the sensitivity of the primary estimates to incomplete or irregular measurement.

The Full Analysis Set includes randomized participants who received at least one dose, analyzed as randomized. The registry does not report the number or characteristics of randomized participants who may not have received a dose, nor does it give detailed participant flow for the primary analysis. Information on adherence to the assigned injection schedules is also not reported in the registry record.

The record does not report a multiplicity plan for the several secondary outcomes and analyses. It also does not provide detailed definitions for every outcome or identify which secondary analyses were prespecified. This limits the confirmatory interpretation of nominal secondary findings. In addition, the registry’s safety summary provides group counts but does not report exposure-adjusted rates, event timing, or a full account of severity and relatedness.

The record describes the study as international and multicenter, but does not provide the country or site distribution in the registry record for this analysis. Eligibility criteria, baseline characteristics, treatment discontinuations, and the sample-size justification are not reported in the registry record. Without those details, readers cannot fully assess representativeness, balance at baseline, or the design assumptions behind enrollment. These are limits of the available registry description, not evidence that the trial did not collect or analyze those details.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy And Safety Evaluation of Glepaglutide in Treatment of Short Bowel Syndrome (SBS) — NCT03690206.
• Registry record last updated 2025-07-17; status last verified 2025-06.
• Results first posted 2024-10-21.
• 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

NCT03690206 is a completed phase 3 randomized, quadruple-masked, parallel-group trial sponsored by Zealand Pharma. It enrolled 106 participants with short bowel syndrome and compared glepaglutide injections twice weekly, glepaglutide once weekly with placebo once weekly, and placebo injections twice weekly.

The primary endpoint was change in weekly parenteral support volume from baseline to Week 24, analyzed in the Full Analysis Set. The registry reports least-squares mean estimates and mixed-model differences to placebo. The twice-weekly comparison had an estimated difference of -2.28 L/week, with a 95% confidence interval from -3.83 to -0.73; the once-weekly comparison had an estimated difference of -0.91 L/week, with a 95% confidence interval from -2.52 to 0.71.

Secondary outcomes cover response, time off support, weaning, and other measures. The registry also reports serious adverse event counts and no deaths in the three groups. Details on missing-data methods, multiplicity, and the full statistical analysis plan are not reported in the registry record.