Glucagon Response to Prandial Insulin Administration in Persons With Type 1 Diabetes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Glucagon Response to Prandial Insulin Administration in Persons With Type 1 Diabetes (NCT04079881), a randomized phase 1, phase 2 study. The primary outcome is AUC Postprandial Glucagon.

2. Clinical Question

The clinical rationale in the registry concerns the relationship between insulin and glucagon regulation in type 1 diabetes. The study description presents a gap in knowledge: whether appropriately timed exogenous insulin can modify glucagon responses to glucose fluctuations in people with undetectable C-peptide. It also frames post-meal glucose as a related question, with postprandial glucose AUC listed as a secondary outcome.

The intended comparison was about timing, not about insulin versus no insulin. Both conditions used short-acting insulin and the participant’s home regimen; the difference described was whether it was given before or after the meal. Because the trial was terminated and its primary analysis was not performed, the record does not establish the direction, size, or precision of any glucagon difference. It also does not report a result for postprandial glucose.

3. Trial Design

The registry describes a randomized, unmasked crossover trial in Phase 1 and Phase 2. The study was sponsored by Washington University School of Medicine. Enrollment was 1. The registry lists the start date as 2020-02-13 and the primary completion date as 2020-07-01, and gives the study status as terminated.

In a crossover design, a participant receives each of the conditions being compared, and the outcomes can be compared within that participant. Here, the conditions were pre-prandial and post-prandial insulin administration. The registry descriptions specify visits in which short-acting insulin was given with the participant’s home regimen, either 20 min prior to the meal or 20 min post the meal. The order was randomized: one listed sequence began with pre-prandial administration, and another began with post-prandial administration.

Randomized order can help prevent a consistent order from being tied to one condition. In a crossover study generally, interpretation also depends on how the visits are scheduled and whether effects from an earlier condition could carry into a later one. The registry record does not report the visit interval, a washout procedure, or details of sequence generation. It does not report whether any planned procedures were completed by the enrolled participant.

The registry identifies the study as unmasked. It does not report procedures to mask participants or study personnel, and the timing of insulin relative to a meal is apparent from the assigned condition. The record does not describe the method used to allocate the participant to a sequence.

The study was delayed and then terminated due to the COVID pandemic, and funding was lost. The primary analysis was not performed. As a result, the design describes the intended comparison, but the registry record does not provide an analyzed treatment effect. The record also does not report a completed crossover comparison, an analysis population, or a statistical model fitted to participant-level outcomes.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Study was delayed and then terminated due to COVID pandemic, funding was lost so primary analysis was not performed.

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: Trial was terminated due to COVID pandemic and loss of funding.

6. Primary Endpoint

The registry lists the primary outcome as AUC Postprandial Glucagon, measured over 4 hours.

The primary endpoint was AUC postprandial glucagon, with a timeframe of 4 hours. AUC represents the accumulated level of a measured quantity across a defined time interval. In general, it can capture the overall response over that interval rather than relying on a single measurement. For a hormone response following a meal, this can be useful when the response changes over time.

The registry describes glucagon measurements at fasting and at 30, 60, 120, and 180 minutes. It does not report the unit for the endpoint, the method used to calculate AUC, or whether the AUC was adjusted for fasting glucagon. Those details therefore cannot be used to interpret a numerical value. The recorded timeframe is 4 hours, while the listed measurement description identifies the time points through 180 minutes; the record does not explain this difference in wording.

The endpoint was intended to compare the glucagon response under pre-prandial and post-prandial insulin timing. The clinical question concerns whether timing modifies glucagon regulation during meal-related hyperglycemia. However, the registry states that the primary analysis was not performed because the study was delayed and terminated due to the COVID pandemic and funding was lost. It therefore reports no primary endpoint estimate, uncertainty interval, or statistical comparison. The endpoint’s role can be described, but the record does not support a conclusion about the observed glucagon response.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods determine how observations are turned into estimates and how much uncertainty is attached to those estimates. The registry record describes the study design and outcomes but does not report a completed primary analysis. Accordingly, the concepts below explain how the planned comparison is generally understood; they are not a description of analyses performed for this trial.

What does a crossover comparison estimate?

In general, a crossover study compares conditions within the same participant. For this trial, the intended contrast was the glucagon response when prandial insulin was administered before a meal versus after a meal. A within-participant comparison can account for stable characteristics shared across a participant’s visits. The relevant outcome contrast would need to be calculated from measurements collected under both conditions.

That contrast is not reported in the registry record. The record does not give participant-level measurements, a summary estimate, or a fitted model. It also does not state how the analysis would account for visit order, period, or possible carryover between conditions. These are general considerations for crossover analyses, not claims that any particular effect occurred in this study.

What does randomization contribute?

Randomizing the order of conditions can reduce the chance that one condition is systematically assigned to a particular sequence. In general, it helps separate a condition comparison from an order effect, but it does not guarantee balance in a very small study or make unreported outcomes available. The registry identifies the trial as randomized and lists sequences beginning with either pre-prandial or post-prandial insulin. It does not report the randomization procedure or allocation details.

The study was unmasked. When a condition is known to participants or study personnel, measurement, behavior, or assessment may be influenced in some settings. Whether any such influence affected this trial is not reported in the registry record. The outcome measurement and analysis procedures needed to assess that possibility are not described in the posted results.

How should AUC be understood?

In general, AUC combines measurements over time into a measure of cumulative response across a defined interval. Its interpretation depends on the time interval, measurement schedule, units, and calculation rule. The primary endpoint is identified as postprandial glucagon AUC over 4 hours, and the description lists fasting and post-meal glucagon measurements at 30, 60, 120, and 180 minutes. The unit and AUC calculation method are not reported in the registry record.

AUC can capture the overall pattern of a response, but it may not reveal every feature of that pattern. For example, an AUC alone does not specify when a peak occurred. The study rationale also mentions peak postprandial blood glucose, but the record does not provide a reported peak value or a primary analysis of that measure. The secondary outcome listed is postprandial glucose AUC, for which no result is posted.

What do precision and statistical significance mean?

In general, a confidence interval describes a range of values compatible with the data and the assumptions of the analysis. A narrower interval indicates greater precision under those assumptions, while a wider interval indicates more uncertainty. A p-value, when reported, summarizes how unusual data at least as extreme as the observed data would be under a specified null hypothesis and model. Neither measure establishes clinical importance on its own.

The registry record reports no confidence interval or p-value for the glucagon comparison, because the primary analysis was not performed. There is therefore no reported estimate whose precision or statistical significance can be interpreted. The absence of an analysis is not a finding of no difference, and it does not establish equivalence between insulin timing conditions.

How should planning illustrations be read?

In general, sample-size calculations are planning exercises: they indicate how many participants might be needed under specified assumptions about an effect, variability, allocation, and analysis. Such calculations do not describe what was observed in a trial. Planning illustrations are not observed power. The assumptions described for illustrations associated with this record include a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects expressed as fractions of an observed effect. The registry’s primary analysis was not performed, so any such illustration cannot provide an analyzed primary result.

Sample-size calculations depend on their assumptions. If an assumed effect is uncertain or does not correspond to a meaningful target, the resulting planning figure may not answer the design question of interest. The registry record does not report the study’s own sample-size justification or protocol rationale. Any planning illustration should therefore be interpreted only as a conditional calculation under its stated assumptions, not as evidence about treatment effect or trial success.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome of postprandial glucagon AUC and a secondary outcome of postprandial glucose AUC. Testing or interpreting multiple outcomes can raise multiplicity concerns: in general, the more comparisons considered, the more important it is to define which result is primary and how additional analyses will be handled. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a statistical analysis plan addressing multiple comparisons.

The primary analysis was not performed, and no secondary outcome results are reported. Consequently, there are no posted estimates to interpret as confirmatory or exploratory findings. The record does not report whether other outcomes or time-point comparisons were planned, so their status cannot be characterized.

Missing-data methods are not reported in the registry record. It does not state whether glucagon or glucose measurements were collected, whether visits were completed, how incomplete measurements would be handled, or whether any imputation or sensitivity analysis was planned. The record likewise does not describe an intention-to-treat, per-protocol, or other analysis population. Although enrollment was 1, the record does not explain which participants or observations would have been included in an analysis.

These omissions limit interpretation independently of the absent outcome analysis. Without an analysis population and missing-data approach, readers cannot determine what data were intended to contribute to an estimate. Without a documented multiplicity strategy, the intended interpretation of any additional comparisons is unclear. None of these details should be inferred from the randomized crossover label 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.

The registry lists safety counts separately for pre-prandial and post-prandial insulin. For each group, 1 participant was recorded as at risk. Each group has 0 serious adverse events, 0 other adverse events, and 0 deaths in the posted counts.

These are counts, not estimates of comparative risk. The registry does not report event definitions, the observation period for these entries, or a statistical comparison between conditions. It also does not give enough information to determine whether the participant completed all planned exposure or observation procedures. The record’s total enrollment was 1, and the same participant may be represented under both crossover conditions; the group entries should not be treated as separate independent groups of people.

In general, zero recorded events in a small study do not establish that the underlying event risk is zero. They mean that no events were listed for the recorded categories and groups in the registry. These counts should be read alongside the fact that the study was terminated and its primary analysis was not performed. They do not support a broad safety conclusion or a definitive comparison of the timing conditions.

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

The registry record documents a planned comparison of short-acting insulin before versus after a meal in a randomized crossover study of people with type 1 diabetes. It identifies postprandial glucagon AUC as the primary endpoint and postprandial glucose AUC as a secondary outcome. The primary endpoint was intended to characterize the glucagon response over 4 hours.

What the record does not provide is an analyzed comparison. The study was delayed and then terminated due to the COVID pandemic, funding was lost, and the primary analysis was not performed. No glucagon effect estimate, confidence interval, p-value, or glucose outcome result is reported. The record therefore cannot show whether the glucagon response differed between insulin timing conditions, how large any difference might have been, or how precise an estimate would be.

This absence of a result should not be interpreted as evidence that the timing conditions had the same effect. It also should not be taken as evidence that one condition changed glucagon or glucose in a particular direction. A protocol description gives the question and intended measurements, while a result requires analyzed observations. For this record, that inferential step is missing.

Enrollment was 1, and the trial was intended as a pilot study. In general, a pilot study can help characterize procedures or inform later research, but it does not automatically provide a reliable estimate for a broader population. Here, the lack of a primary analysis means even a pilot estimate is not available in the registry record. Generalization to other people with type 1 diabetes is not supported by a reported treatment effect.

The posted safety counts list no serious adverse events, other adverse events, or deaths in either group, with 1 participant at risk in each. Those counts are descriptive and do not establish that the conditions have no safety risks. Overall, the registry provides a record of the research question, design, endpoints, termination, and recorded safety counts, but not evidence that resolves the intended clinical comparison.

13. Why This Trial Matters Statistically

This trial illustrates the distinction between a registered research question and an interpretable statistical result. The question is specific: compare glucagon response when prandial insulin is administered before versus after a meal. The registry identifies a primary endpoint and a crossover design suited in principle to a within-participant timing comparison. Yet the primary analysis was not performed, so the central estimate needed to answer the question is absent.

That distinction matters when reading clinical research records. A detailed rationale, endpoint description, and measurement schedule can explain what investigators intended to study, but they do not reveal the observed outcome. Statistical interpretation requires results together with uncertainty, analysis methods, and information about which observations were included. Those elements are not reported for the primary comparison in this record.

The record also makes visible how enrollment and study completion affect what can be learned. Enrollment was 1, and the study was terminated after delay related to the COVID pandemic and loss of funding. A crossover design can be efficient in general, but design efficiency cannot substitute for collected and analyzed data. Nor can a planning calculation replace a treatment estimate; planning illustrations are conditional scenarios, not observed power or evidence of an effect.

For clinical researchers and biostatisticians, the case emphasizes the value of transparent reporting of outcome analyses, uncertainty, missing-data handling, analysis populations, and crossover-specific methods. Such reporting helps readers distinguish an imprecise result from an unperformed analysis, and a null finding from a question left unanswered. Here, the registry documents the question and why the planned primary analysis is unavailable, while leaving the comparative glucagon result unresolved.

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 principal limitation is that the primary analysis was not performed. No treatment estimate or uncertainty measure for postprandial glucagon AUC is reported, so the intended contrast cannot be evaluated statistically. No result for the listed secondary outcome, postprandial glucose AUC, is reported either.

Enrollment was 1. This makes the registered study very limited in scale, and the record does not report an analyzed participant-level comparison. It does not provide participant characteristics, confirm the planned target-population features for the enrolled participant, or describe whether the participant completed both conditions. The record therefore does not establish the completeness of the intended crossover data.

Some design details that would inform interpretation are not reported in the registry record. These include the interval between visits, any washout procedure, the process used to generate the randomized sequence, and the planned handling of order or period effects. The endpoint unit and AUC calculation method are also not reported. These gaps cannot be filled by assuming standard procedures.

The study status is terminated, and the record attributes this to delay due to the COVID pandemic and loss of funding. It does not explain whether any outcome measurements had been collected before termination, or why the primary analysis was not available beyond the stated circumstances. Missing-data handling, analysis populations, and any planned sensitivity analyses are not reported.

The safety counts are limited and descriptive. The registry does not report event definitions or observation duration, and the small enrollment does not support broad safety conclusions. Taken together, these limitations mean that the record describes an intended pilot comparison but cannot provide a quantitative conclusion about the effect of insulin timing on glucagon or glucose responses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Glucagon Response to Prandial Insulin Administration in Persons With Type 1 Diabetes — NCT04079881.
• Registry record last updated 2022-10-07; status last verified 2022-09.
• Results first posted 2022-03-02.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04079881 is a randomized, unmasked crossover study listed in Phase 1 and Phase 2, sponsored by Washington University School of Medicine. It compared short-acting insulin given 20 min prior to a meal with insulin given 20 min post the meal. Enrollment was 1.

The primary endpoint was postprandial glucagon AUC over 4 hours, with glucagon measurements described as fasting and at 30, 60, 120, and 180 minutes. Postprandial glucose AUC was listed as a secondary outcome. The study was delayed and then terminated due to the COVID pandemic, funding was lost, and the primary analysis was not performed. No primary or secondary outcome result is reported in the registry record.

For each insulin timing group, the registry lists 1 participant at risk, 0 serious adverse events, 0 other adverse events, and 0 deaths. These counts are descriptive and do not establish comparative safety. The record documents the intended question and study design but does not resolve whether insulin timing changed the glucagon response.