Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia (NCT04652479), a randomized phase 2 study. The primary outcome is Diurnal Level 2 Hypoglycemia Events (ADA, <54 mg/dL) as Measured by CGM in Patients With Severe Hyperinsulinemic Hypoglycemia (HH).

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, open-label, cross-over study of avexitide for acquired hyperinsulinemic hypoglycemia. The registry record lists enrollment of 25 participants and a completed study. The study started on 2021-06-21, with primary completion on 2022-06-30. Those dates describe the study timeline; they do not indicate when individual participants began or finished treatment.

In a cross-over design, participants receive more than one study treatment over different periods. In this study, each participant was assigned to one of two sequences: avexitide 45 mg twice daily followed by 90 mg once daily, or 45 mg once daily followed by 90 mg twice daily. Each treatment period lasted 14 days. The primary endpoint also included a 14-day run-in period. Randomization assigned the treatment sequence, while the absence of masking means the study was open-label.

General statistical context: a cross-over design can support comparisons that account for measurements from the same participant under different treatments. Those measurements are correlated, rather than independent. The design can also be sensitive to period effects, sequence effects, and carryover from an earlier treatment period. The registry record does not report a washout period, how these potential effects were handled, or the statistical model used to account for within-participant comparisons.

The posted record identifies avexitide as the intervention and lists secondary outcomes covering hypoglycemia measured by self-monitoring of blood glucose and CGM, as well as postprandial glycemia during a standardized mixed meal. It lists 6 outcome measures and 12 analyses. Further details about allocation procedures, protocol deviations, and analysis methods are 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: 25 participants entered a 14-day run-in (screening) period during which they wore the continuous glucose monitor (CGM). 17 participants who had at least 2 hypoglycemic events were randomized to a study arm.

Run-in Period (14 Days)

Treatment Period 1 (14 Days)

Washout Period (2 Days)

Treatment Period 2 (14 Days

Analysis population for the primary outcome, as defined in the registry: Participants with no major protocol deviations who were allocated to treatment.

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: Participants with no major protocol deviations who were allocated to treatment.

6. Primary Endpoint

The registry lists the primary outcome as Diurnal Level 2 Hypoglycemia Events (ADA, <54 mg/dL) as Measured by CGM in Patients With Severe Hyperinsulinemic Hypoglycemia (HH), measured over Run-in period (14 days), treatment period 1 (14 days), and treatment period 2 (14 days).

The primary endpoint is the rate of diurnal Level 2 hypoglycemia events measured by CGM in participants with severe hyperinsulinemic hypoglycemia. Level 2 hypoglycemia is defined in the record using the American Diabetes Association threshold of glucose <54 mg/dL. The measurement covers diurnal hours, defined as 8am-10pm, and counts events captured by CGM during the run-in and treatment periods.

For each period, glucose data were collected for 14 days. The recorded event count was divided by the number of days and then normalized to a 14-day duration. The stated unit is events per 14 days. This rate-based expression makes the endpoint interpretable over a common duration, while the underlying observation is a count of detected events. It is not the same as a measure of how long a participant spent below the glucose threshold.

General statistical context: an event rate can be useful when the amount of observation or exposure time matters. Rates describe event frequency over a defined duration, while a mean summarizes the average value across observations and a standard deviation describes their spread. The registry lists the endpoint parameter as a mean with standard deviation. It does not report the numerical mean or standard deviation for the primary outcome, nor an estimate of the comparison between treatment periods. The reason for selecting this endpoint is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the event rate represent?

The primary outcome is a rate of CGM-detected Level 2 hypoglycemia events, reported in events per 14 days. The registry describes counting events with glucose measures <54 mg/dL during diurnal hours, 8am-10pm. It also describes dividing the event count by the number of days of collected data and normalizing the result to a 14-day duration. This places the period summaries on a common time scale.

General statistical context: counts and rates are related but answer different questions. A count gives the number of events recorded; a rate relates that count to a defined amount of observation time. A rate is useful when observation duration may differ or when results need a common exposure period. Here, the registry specifies 14 days of data collection per period and reports the rate per 14 days. The endpoint is distinct from percentage of time spent below a glucose threshold, which is listed among the secondary outcomes.

Why report a mean and standard deviation?

The primary endpoint is designated as a mean with standard deviation. A mean describes the average of participant-level outcome values in a group or period. The standard deviation describes how much those values vary around the mean. It does not, by itself, describe the precision of the estimated mean; a confidence interval is commonly used for that purpose. No primary mean, standard deviation, or confidence interval is reported in the registry record.

General statistical context: event data can be skewed, and counts may vary more than a simple probability model expects. Over-dispersion means that the observed variation exceeds what a model assumes. If a rate outcome is over-dispersed, a model that fails to account for that extra variation can give uncertainty estimates that are too small. The registry record does not identify a count model, an over-dispersion assessment, or an alternative distribution for this endpoint, so it is not possible to determine how this issue was addressed.

What does the cross-over structure imply?

Participants were randomized to a sequence of two avexitide dosing regimens, and each regimen was given for 14 days. In a cross-over study, each participant contributes information under more than one treatment. General statistical context: such measurements are not independent, because values from one participant may be more alike than values from different participants. An analysis can account for this within-participant correlation and can estimate a treatment contrast while recognizing the paired structure.

Cross-over analyses also need to consider whether outcomes change over time independently of treatment, whether the sequence assigned matters, and whether an earlier treatment affects measurements in a later period. Those questions are especially relevant when treatment periods follow one another. The registry record does not report a washout period, a test for carryover, or the model used to account for participant, period, or sequence. It is therefore not possible to establish from the registry record whether these design features were addressed in the analysis.

How should uncertainty and significance be read?

General statistical context: a confidence interval communicates uncertainty around an estimated effect, conditional on the data and analysis assumptions. A narrower interval generally indicates greater precision than a wider interval, though precision alone does not establish clinical importance. A p-value measures how compatible the data are with a specified null hypothesis under the chosen model. It is not the probability that the null hypothesis is true, and it does not show the magnitude of an effect.

No primary treatment contrast, confidence interval, or p-value is reported in the registry record. The record also does not describe the prespecified statistical test or model. Consequently, no inferential conclusion about the primary endpoint can be drawn from the registry information presented.

What can planning calculations tell readers?

The record describes planning illustrations based on a fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. Such illustrations ask how many participants per arm might be needed under stated assumptions to detect a chosen effect. They are conditional calculations, not measurements of the trial’s performance.

General statistical context: observed power calculated after a study from its observed effect does not replace an effect estimate and confidence interval. Planning calculations are sensitive to assumptions about the effect size and variability. They should be interpreted as illustrations, not as the probability that the study detected a real effect. The registry record does not report the trial’s own sample-size justification or numerical primary outcome estimates. It is therefore not possible to assess the planning assumptions against the actual primary result from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures and 12 analyses. The primary outcome is specified as diurnal Level 2 hypoglycemia events measured by CGM, while the secondary outcomes include hypoglycemia measures using self-monitoring of blood glucose and CGM, and postprandial glycemia during a standardized mixed meal. The existence of multiple outcomes and analyses raises a general multiplicity issue: when many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for the number and structure of tests.

The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or which comparisons were treated as confirmatory. It also does not report a full statistical analysis plan, so the handling of repeated comparisons across treatment periods and outcome measures is not reported in the registry record. The primary result itself is not reported in the registry record.

The primary outcome population is described as participants with no major protocol deviations who were allocated to treatment. The registry does not report how many participants met that definition or how exclusions were handled. It also does not report whether an intention-to-treat population or another analysis population was used for other outcomes.

Missing data handling is not reported in the registry record. This includes how missing CGM readings, incomplete period data, or withdrawals were handled, if any occurred. General statistical context: missingness can affect both the amount of information available and the comparability of treatment-period summaries. Its impact depends on why observations are missing and on the analysis assumptions. Without reporting of missingness and its handling, readers cannot assess its influence on the endpoint estimates.

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 non-serious adverse event terms

The registry reports serious adverse event counts for the run-in period and for each avexitide regimen. In the run-in period, 25 participants were at risk and 0 had a serious adverse event. For avexitide 45 mg twice daily, 17 participants were at risk and 0 had a serious adverse event. For avexitide 90 mg once daily, 17 participants were at risk and 0 had a serious adverse event. The registry reports 0 deaths in each of these groups.

The registry separately lists other adverse events affecting 0 participants during run-in, 7 participants during avexitide 45 mg twice daily, and 8 participants during avexitide 90 mg once daily. These are counts of participants affected, not event rates per 14 days. The record does not provide the specific terms for serious adverse events and lists no top serious terms.

General statistical context: a zero count does not establish that an event is impossible or that the treatments are equivalent in safety. Safety counts need to be interpreted alongside the number observed, the duration of observation, event definitions, and the completeness of reporting. Because this is a cross-over study, participants may contribute to both treatment periods; the period counts should not be added as though they necessarily represent distinct people. The registry counts describe events and affected participants but do not establish causation.

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

The registry record establishes that a completed, randomized, open-label, phase 2 cross-over study assessed two avexitide dosing regimens in acquired hyperinsulinemic hypoglycemia. It also describes a primary endpoint based on diurnal CGM-detected Level 2 hypoglycemia events, measured during a run-in period and both treatment periods. These design details define what the study set out to examine.

They do not establish what the primary endpoint showed. Numerical results for the primary outcome, including event-rate estimates and comparisons, are not reported in the registry record. Without those results, readers cannot determine whether the observed event rate was higher or lower in one treatment period, how large any difference was, or how precisely it was estimated. The stated aim to assess efficacy is not itself a result.

The registry does report safety counts. It lists no serious adverse events and no deaths in the run-in period or either treatment group, while other adverse events affected participants during the treatment periods. These descriptive counts do not establish that avexitide caused or prevented any event, and they are not a complete statistical comparison of safety. The record does not provide event terms for serious events or details about attribution.

General statistical context: a treatment comparison is best interpreted using both an effect estimate and its uncertainty. A statistical test alone cannot explain clinical importance, and a sample-size planning illustration cannot stand in for observed results. The registry record does not report the primary effect estimate, its uncertainty, the analysis model, or the trial’s own sample-size justification. The appropriate conclusion is therefore limited to the study design and reported safety counts, not a conclusion about the comparative efficacy of the regimens.

These limits concern what can be learned from the registry record; they do not establish that results were never collected or analyzed. The record does not report whether results are available elsewhere. The available information supports a description of the question and methods, but not a determination of the primary endpoint’s outcome.

13. Why This Trial Matters Statistically

This trial is statistically notable for its cross-over design and rate-based primary endpoint. Participants were randomized to treatment sequences and received both avexitide regimens, each for 14 days, after a 14-day run-in period. That structure means the main comparison involves repeated measurements within participants rather than unrelated groups alone. A suitable analysis needs to preserve that structure when estimating treatment differences and uncertainty.

The endpoint also illustrates why an outcome definition matters. It counts CGM-detected glucose events below the Level 2 threshold during diurnal hours and expresses the result as events per 14 days. That is different from measuring the percentage of time below a threshold or counting all hypoglycemia events regardless of level. The registry lists both time-based measures and other hypoglycemia outcomes among its secondary outcomes, making clear that these endpoints represent distinct summaries.

The record also highlights the distinction between a study’s purpose and its reported findings. A phase 2 study can be designed to assess safety and efficacy, but interpretation requires the observed estimates and their uncertainty. Here, the primary outcome results and statistical analysis details are not reported in the registry record. Without them, it is not possible to judge the comparative size or precision of the primary treatment effect.

Finally, the safety record illustrates the limits of sparse event counts. Zero serious adverse events were recorded in the stated groups, while other adverse events affected participants during treatment. These figures are informative as registry counts, but they do not alone establish comparative safety or causation. Together, the design and reporting demonstrate why endpoints, analysis populations, missing data handling, and uncertainty are central to interpreting a clinical trial.

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 registry record does not report numerical results for the primary endpoint. This is the main limitation for statistical interpretation: the event-rate means, standard deviations, treatment contrast, confidence interval, and p-value are not available. The direction, magnitude, and precision of the primary comparison therefore cannot be assessed.

Further methodological details are also not reported in the registry record. These include the randomization procedure, the statistical model, how within-participant correlation was handled, and how period, sequence, or carryover effects were considered. The record does not describe a washout period. These details matter in a cross-over design because each participant receives both dosing regimens over time.

The primary analysis population is described as participants allocated to treatment with no major protocol deviations, but the number in that population and the handling of exclusions are not reported. Missing CGM measurements and incomplete treatment periods are not described, and missing data methods are not reported. The registry also does not report a multiplicity plan for the listed outcomes and analyses or the trial’s own sample-size justification.

The safety information is limited to counts of participants at risk and affected, along with deaths and serious adverse events. Specific serious adverse event terms are not listed, and the record does not describe attribution to treatment or the approach to collecting and classifying events. Because the study is cross-over, counts from the treatment periods should not be interpreted as distinct groups of participants without further information. These limitations restrict what can be concluded from the registry record alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia — NCT04652479.
• Registry record last updated 2023-06-09; status last verified 2023-05.
• Results first posted 2023-06-09.
• 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

NCT04652479 is a completed phase 2, randomized, open-label, cross-over study of avexitide for acquired hyperinsulinemic hypoglycemia. Enrollment was 25. The study started on 2021-06-21, and primary completion was 2022-06-30.

Participants were assigned to one of two treatment sequences, with each avexitide regimen given for 14 days. The primary endpoint was diurnal Level 2 hypoglycemia events measured by CGM, expressed as events per 14 days, across a 14-day run-in period and both treatment periods. The primary endpoint results are not reported in the registry record.

The registry lists zero serious adverse events and zero deaths in the run-in period and each treatment group. Other adverse events affected 7 participants during avexitide 45 mg twice daily and 8 during avexitide 90 mg once daily. The record does not report the detailed statistical analysis plan, missing data methods, or multiplicity handling.