A Study to Determine Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Type 1 Diabetes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Determine Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Type 1 Diabetes (NCT04118374), a randomized na study. The primary outcome is Change in Insulin Sensitivity Assessed as Glucose Infusion Rates.

2. Clinical Question

The study addresses whether changing carbohydrate intake is associated with a change in insulin sensitivity in this study population. Its primary endpoint is glucose infusion rate, expressed per kilogram of fat-free mass per minute. The registry also describes a broader interest in blood vessel health, but it lists one outcome measure and does not provide a posted secondary outcome result.

This is a within-participant comparison: each analyzed participant received both diets. That structure makes the question about the difference between diet periods within the crossover study, rather than a comparison of two separate groups of participants. The registry does not report enough detail to establish how any period or sequence effects were handled in the analysis.

3. Trial Design

The registry describes a randomized, open-label crossover study of a standard carbohydrate diet and a low carbohydrate diet in people with type 1 diabetes. Participants received both interventions. The registry states that participants completed each diet for one week, with a three-week washout between diet periods. Allocation was randomized, and masking was not used.

The primary outcome was change in insulin sensitivity assessed as glucose infusion rate, with measurements identified at week 1 and week 5. The outcome description says insulin sensitivity was measured after each intervention using a hyperinsulinemic-euglycemic clamp. Glucose infusion rate was expressed in mg/kg FFM/min after dividing the dextrose infusion rate by fat-free mass determined by DEXA.

The registry lists enrollment of 14 and says 12 participants received both interventions and were included in the analysis. It does not report why the analysis population is smaller than the enrollment figure, whether any participants had incomplete outcome measurements, or how missing observations were handled.

The trial status is completed. The recorded start date is 2021-11-24 and the primary completion date is 2024-06-21. The registry names Vanderbilt University Medical Center as the sponsor. It does not report a detailed rationale for the sample size, a statistical analysis plan, or information about interim analyses. The sequence descriptions do not add details about the conduct of either diet period.

In a crossover design, each participant serves as their own comparator. This can reduce the influence of stable differences between participants, but interpretation can depend on the order of treatments, changes over time, and whether effects carry into the next period. The registry reports a washout interval but does not report analyses of period, sequence, or carryover effects. Those details should not be inferred from the design label alone.

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: In the full study, 14 participants enrolled and completed the screening visit. Two did not proceed past the run-in period due to scheduling conflicts and inconsistent nutrition logging.

First Intervention (7 days)

Washout Period (21 days)

Second Intervention (7 days)

Analysis population for the primary outcome, as defined in the registry: 12 participants received both interventions in this crossover study and were included in the analysis.

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 Insulin Sensitivity Assessed as Glucose Infusion Rates, measured over week 1 and week 5.

The primary endpoint is insulin sensitivity assessed through glucose infusion rate during a hyperinsulinemic-euglycemic clamp. The registry reports the measure in mg/kg FFM/min. It describes dividing the dextrose infusion rate by fat-free mass measured by DEXA, so the reported rate is expressed relative to body composition rather than as an unscaled infusion amount.

In general, a clamp is used to assess how much glucose must be infused to maintain the target glucose condition while insulin is infused. Under the measurement conditions, a higher glucose infusion rate is generally interpreted as greater insulin sensitivity. This is a general explanation of the measure; the registry does not provide additional procedural details about the clamp protocol.

The registry reports medians and inter-quartile ranges for the endpoint. The median is a measure of the center of a distribution, while the inter-quartile range describes the span of the middle half of observed values. These summaries describe the outcome within each diet period, but by themselves do not give the distribution of paired within-participant differences. The registry identifies the outcome timeframe as week 1 and week 5 and says measurement followed each intervention.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the crossover design mean?

In a crossover study, participants receive more than one intervention in separate periods. Comparisons can use the fact that the same participant contributes outcome information under both conditions. In general, this can reduce the effect of stable characteristics that differ between people, because those characteristics are shared across a participant's own treatment periods. It does not automatically eliminate bias or ensure that a simple comparison is appropriate.

For this study, the registry reports random assignment to diet sequences, receipt of both diets, and a three-week washout between the one-week diet periods. The record does not report the sequence-specific results or explain whether the analysis included period or sequence terms. It also does not report an assessment of carryover. A washout is intended to reduce the chance that an earlier intervention affects a later period, but the presence of a washout alone does not demonstrate that carryover was absent. These are general design considerations, not claims about what occurred in this trial.

Why report medians and inter-quartile ranges?

A median is the central value after observations are ordered. It can be useful when a distribution is skewed or when extreme values could strongly affect a mean. The inter-quartile range covers the middle half of the distribution and gives information about spread. These summaries help describe the outcome after each diet, but separate medians and ranges do not show the paired changes for individual participants. In a crossover study, the distribution of within-participant differences can be important for estimating the treatment contrast.

The registry identifies the outcome parameter as a median and the dispersion as an inter-quartile range. It gives medians of 8.6 mg/kg FFM/min for the standard carb diet and 8.1 mg/kg FFM/min for the low carb diet, with the respective inter-quartile ranges reported as 7.0 to 11.0 and 6.7 to 10.1. The posted analysis is described as an ANOVA and as a median difference in final values. The registry does not provide further detail about the model specification, transformations, or how these summaries relate to the inferential procedure.

How should the confidence interval and p-value be read?

In general, a confidence interval expresses uncertainty around an estimated contrast under the statistical model. Its width reflects the precision of the estimate: a wider interval allows a broader range of plausible values. For a difference, zero represents no difference. A confidence interval that includes zero does not establish a difference in either direction at its stated confidence level.

A p-value is a measure of compatibility between the data and a null hypothesis under model assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The registry reports a 95% confidence interval from -0.5 to 1.8 alongside p <0.01. As recorded, the interval includes zero while the p-value is below 0.01. Those entries would ordinarily point to different conclusions about statistical significance when paired in a conventional two-sided analysis. The registry record does not report enough information to reconcile them, so neither should be silently substituted for the other.

Why does the analysis method matter?

ANOVA is a family of methods for comparing means or modeled effects under a specified model. In general, model structure and assumptions matter, particularly when observations are paired, repeated, or clustered. The word ANOVA alone does not tell a reader which terms were included or whether the model accounted for the crossover periods. The registry record does not report those details, so they cannot be inferred from the method label.

Over-dispersion is a general concern when observed variability is greater than a model assumes. If a model underestimates variability, uncertainty can appear too small and tests can appear more decisive than warranted. The registry record does not report an over-dispersion assessment, and no conclusion about it can be drawn from the posted summaries.

What can planning illustrations tell readers?

Sample-size planning illustrations are hypothetical calculations under stated assumptions; they are not observed power. The registry's planning description refers to a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a fraction of the observed effect. Such illustrations depend on the assumptions used and do not show that the completed study had a particular probability of detecting an effect. The trial's own sample-size justification is not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry reports the sponsor's inferential analysis as an ANOVA comparing the final values, with a median difference of 0.2, a 95% confidence interval from -0.5 to 1.8, and p <0.01. The outcome description separately states that insulin sensitivity showed no significant difference between diets. The interval includes zero, while the reported p-value is below 0.01; the registry does not explain this lack of alignment.

No separate unadjusted recalculation of the comparison is reported in the registry record. The posted diet-specific medians and inter-quartile ranges are descriptive summaries and do not supply the paired participant-level differences needed to reconstruct a crossover comparison. They should not be used to replace the sponsor's analysis or to infer a new p-value or confidence interval.

The sponsor's reported result should therefore be quoted with its uncertainty and with the inconsistency made explicit, rather than reduced to a single claim of statistical significance or non-significance. The record does not report further analysis details that would resolve the interpretation.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and no posted secondary outcome results. That record does not establish how many outcomes, comparisons, or analyses were planned outside the posted results, nor whether any adjustment for multiple testing was used. A multiplicity strategy is not reported in the registry record. Without that information, the reported p-value cannot be interpreted in the context of an established family of statistical tests.

The registry says 12 participants received both interventions and were included in the analysis, while enrollment is recorded as 14. The reasons for this difference are not reported in the registry record. It does not state whether participants withdrew, whether any outcome measurements were missing, or whether all recorded observations were included. A missing-data method, if one was used, is not reported. The analysis population is described, but the record does not provide a participant flow or a detailed account of exclusions.

The primary endpoint is identified at week 1 and week 5, and the description says measurement followed each diet period. The registry does not report how observations from each period were handled when forming the inferential comparison. It also does not report whether any participants had incomplete data for one diet period or how such data would affect analysis.

The statistical analysis plan, sample-size justification, and interim analysis details are not reported in the registry record. Their absence means readers cannot determine from the record whether the posted analysis followed a prespecified plan or whether other planned analyses were conducted. These gaps do not prove that such procedures were absent; they mean that their details are not reported in the registry record.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports no serious adverse events in either diet group. For non-serious adverse events, it records 2 affected participants in the standard carb diet group and 1 in the low carb diet group. No deaths are reported in either group, and no serious adverse event terms are listed.

These figures are descriptive counts from the registry. They do not, by themselves, establish whether an event was caused by a diet, how severe the non-serious events were, or whether the groups differ in risk. The registry does not provide event descriptions or additional context about timing and attribution.

Because participants received both interventions in a crossover study, the diet groups should not be read as independent parallel groups of participants. The record does not explain whether the adverse-event counts represent people affected during each period or how events occurring across periods were handled. The counts are therefore best read as the posted safety summary, not as a basis for a comparative safety conclusion.

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

The result addresses a specific measurement of insulin sensitivity: glucose infusion rate after a one-week standard carb diet period and after a one-week low carb diet period, with a three-week washout between periods. The reported medians are 8.6 mg/kg FFM/min after the standard carb diet and 8.1 mg/kg FFM/min after the low carb diet. These summaries describe the observed outcome in the analyzed crossover study.

The result does not establish that one diet improves or worsens insulin sensitivity. The registry narrative says there was no significant difference, while the reported p-value and confidence interval are not aligned under conventional interpretation. The confidence interval spans zero, and the record does not explain the discrepancy between that interval and p <0.01. The statistical evidence should therefore be read cautiously rather than as a clear positive or negative finding.

The study also does not establish effects on blood vessel health from the posted primary endpoint. Although the study summary describes interest in blood vessel health, the registry lists one outcome measure and no posted secondary results. The primary outcome is insulin sensitivity assessed by glucose infusion rate.

In general, statistical significance and clinical importance are different questions. A p-value does not indicate the size or practical importance of an effect, and a confidence interval describes statistical uncertainty rather than clinical consequences. The registry record does not provide a threshold for an important change in glucose infusion rate, so the practical importance of the observed summaries cannot be determined from these results alone.

The findings are also limited to the participants and procedures recorded for this study. The registry does not report enough detail to assess the effects of diet sequence, period, or carryover, or to establish how missing data were handled. Results from this crossover study should not be generalized beyond the evidence recorded without considering those limitations.

14. Why This Trial Matters Statistically

This trial is statistically informative because it uses a crossover design to compare two diets within participants. In general, a within-participant design can help control for stable differences between people, but it requires attention to period, sequence, and possible carryover effects. The registry reports randomization and a washout interval, while the details needed to evaluate those design features in the analysis are not reported.

The record also illustrates why descriptive summaries and inferential statistics answer different questions. Diet-specific medians and inter-quartile ranges describe the observed distributions. A treatment comparison requires an estimate and uncertainty that reflect the design. In a crossover study, the paired differences are especially relevant, and the registry does not provide participant-level data or a detailed model specification from which to assess them.

Finally, the reported inferential entries call for careful reading: the confidence interval includes zero, but the p-value is listed as p <0.01. The registry does not explain how these results can be reconciled. Making that uncertainty explicit is more informative than treating one statistic as definitive or relying only on the narrative statement that there was no significant difference.

These features make the record useful for understanding both the promise and the demands of crossover analysis. The design can make efficient use of within-participant comparisons, but interpretation depends on adequate reporting of the analysis and uncertainty. Here, the central statistical question is not only what the median glucose infusion rates were, but also how the study estimated and tested the difference between diet periods.

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.

Several trial-specific details needed to interpret the comparison are not reported in the registry record. Although the study is described as randomized and crossover, the record does not describe the statistical model beyond naming ANOVA, or state how the analysis handled the within-participant pairing, period, diet sequence, or possible carryover. The three-week washout is reported, but its adequacy cannot be assessed from the record.

The inferential result is difficult to interpret as posted. The 95% confidence interval from -0.5 to 1.8 includes zero, while the reported p-value is p <0.01. The registry does not explain the difference between these entries, and its narrative says there was no significant difference. This ambiguity limits any firm reading of the statistical conclusion.

The registry reports enrollment of 14 and analysis of 12 participants who received both interventions, but does not report the reasons for the difference, participant flow, or missing-data handling. It also does not provide participant-level paired results, which would help readers understand the within-person variation underlying the comparison.

The record lists no secondary outcome results despite the broader study summary mentioning blood vessel health. It does not report a multiplicity plan, a sample-size justification, or an analysis plan. Masking was not used. These limitations do not establish that the study procedures were inadequate; they identify information that is not reported and that constrains interpretation of the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Determine Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Type 1 Diabetes — NCT04118374.
• Registry record last updated 2025-10-28; status last verified 2025-09.
• Results first posted 2025-10-28.
• 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

This completed, randomized, open-label crossover study examined insulin sensitivity after a standard carbohydrate diet and a low carbohydrate diet in people with type 1 diabetes. Participants received both one-week diet interventions, separated by a three-week washout. The primary endpoint was glucose infusion rate in mg/kg FFM/min, measured using a hyperinsulinemic-euglycemic clamp.

The registry reports analysis of 12 participants. The median glucose infusion rates were 8.6 mg/kg FFM/min after the standard carb diet and 8.1 mg/kg FFM/min after the low carb diet. The reported 95% confidence interval includes zero, while the listed p-value is p <0.01; the record does not explain this inconsistency. No secondary outcome results are posted. The registry does not report detailed handling of missing data, period and sequence effects, or the statistical analysis plan.