Effect of Formoterol on the Counterregulatory Hormonal Response to Hypoglycemia in Type 1 Diabetes.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Formoterol on the Counterregulatory Hormonal Response to Hypoglycemia in Type 1 Diabetes. (NCT01194479), a randomized na study. The primary outcome is Glucagon (pg/mL).

2. Clinical Question

The clinical rationale in the registry is that insulin treatment can lead to low blood glucose, while the body’s hormonal response to hypoglycemia may be altered in people with diabetes. Glucagon is the hormone named as the primary outcome because the trial aimed to assess the counterregulatory hormonal response. The registry also lists average blood glucose levels as a secondary outcome.

The primary outcome description specifies measurements throughout the study session, including checks every 20 minutes during the 120 minute session. It identifies euglycemia at 30 minutes and hypoglycemia at 105-120 minutes, as well as a basal stage. However, numerical glucagon results for those stages are not reported in the registry record. Without those values or a reported comparison estimate, the clinical question can be described, but the size and direction of any observed difference cannot be assessed.

3. Trial Design

The registry record identifies NCT01194479 as a completed randomized, double-masked crossover study. Enrollment was 14. The study is listed with phase NA and was conducted by Yale University. The recorded start was 2010-08, and primary completion was 2014-08.

The intervention entries are Formoterol, classified as a drug, and Placebo, classified as other. A crossover design generally means that participants receive more than one study condition in a planned sequence, allowing comparisons within participants. Randomization concerns how study assignments or sequences are allocated, while masking is intended to limit the influence of knowledge about assignment. These are general descriptions of the design terms; the particular sequence, timing between conditions and washout procedures are not reported in the registry record.

The registry lists descriptions for Type 1 Diabetics and Healthy Volunteers. It characterizes the former as participants with type 1 diabetes and the latter as participants without diabetes, matched by sex, age and BMI to the active comparator group. The primary outcome description, however, says results are pooled at arm level and split by placebo and control regardless of randomization order. The relationship between these labels and the two participant descriptions is not fully explained in the registry record. The safety groups are listed separately as Control: Placebo, Control: Formoterol, Type 1 Diabetics: Placebo and Type 1 Diabetics: Formoterol.

The study status is completed. The registry identifies four outcome measures, but numerical primary glucagon results are not reported in the registry record. The record lists average blood glucose levels as a secondary outcome. It does not report the detailed allocation sequence, the timing of each treatment period, the washout interval, or the rationale for the enrollment target. These details should not be inferred from the crossover 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Results are pooled at the arm level and split by placebo and control regardless of randomization order.

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 Glucagon (pg/mL), measured over up to 120 minutes.

The primary endpoint is glucagon concentration, expressed in pg/mL and summarized using a mean with standard error as the stated measure of dispersion. Glucagon is relevant to the study question because the registry describes it as part of the counterregulatory hormonal response to hypoglycemia. The aim was to assess whether levels changed during hypoglycemia with inhaled formoterol.

The measurement schedule is described as repeated checks every 20 minutes during a 120 minute study session. The registry identifies results at the basal stage, euglycemia at 30 minutes, and hypoglycemia at 105-120 minutes. These stages provide context for interpreting the hormone measurement: a concentration at a particular stage is not, by itself, a treatment contrast. Assessing a treatment effect would require a clearly defined comparison between the formoterol and placebo conditions, together with the relevant estimates and uncertainty.

The registry describes results as pooled at arm level and split by placebo and control regardless of randomization order. It does not provide numerical glucagon values, a treatment-effect estimate, a confidence interval or a p-value in the record available for this analysis. Consequently, the endpoint’s purpose and measurement plan can be explained, but its observed pattern and the precision of a treatment comparison cannot be described. Average blood glucose levels are listed as a secondary outcome, not as the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover design contribute?

In a crossover study, participants can receive different study conditions in a planned sequence. A within-participant comparison can reduce the impact of stable differences between people, because each participant may contribute observations under more than one condition. That general advantage does not remove the need to account for the sequence and timing of treatments, possible period effects, or carryover from an earlier condition. The registry identifies a randomized crossover design but does not report the sequence structure, washout procedures or the statistical method used to handle these issues.

Double masking means that the study is described as masked at two levels, but the identities of those levels and the procedures used to maintain masking are not reported in the registry record. Masking can reduce the influence of expectations on care, measurement or reporting, depending on how it is implemented. The design label alone does not establish that masking was successful.

How should a mean and standard error be understood?

Glucagon is a continuous measure, and the registry specifies a mean with standard error. A mean describes the central value of the observations being summarized. The standard error describes the uncertainty in an estimated mean under the assumptions of the analysis; it is not the same quantity as the spread of individual measurements. A standard deviation, by contrast, describes variability among observations. The registry names standard error as the dispersion measure but does not report the actual means or standard errors.

When comparing treatment conditions, the most direct statistical quantity is an estimate of the contrast between them, accompanied by a measure of uncertainty such as a confidence interval. A confidence interval expresses a range of values compatible with the observed data under the analysis assumptions. It does not guarantee that the true effect lies in that range, and it does not by itself establish clinical importance. The registry record does not report a glucagon contrast or confidence interval.

Why does the measurement schedule matter?

The endpoint description lists repeated measurements throughout a 120 minute study session, with checks every 20 minutes. It highlights basal, euglycemia at 30 minutes and hypoglycemia at 105-120 minutes. Measurements taken over time are related within a participant, so they should not automatically be treated as independent observations. An analysis of repeated measurements may account for this correlation and may focus on a prespecified time point, a change over time, or a treatment-by-time pattern. The registry record does not report which analytical approach was used or which specific contrast was designated for inference.

The record also says primary results were pooled at arm level and split by placebo and control regardless of randomization order. Pooling may conceal distinctions among participant groups or treatment sequences if those distinctions are relevant to the question. The record does not explain the intended interpretation of these pooled summaries, so they should not be treated as a fully specified analysis plan.

What can significance testing establish?

A significance test evaluates how compatible the observed data are with a specified null hypothesis, conditional on the model and its assumptions. A p-value is not the probability that the null hypothesis is true, nor is it a measure of the size or importance of an effect. Interpreting a test requires knowing the comparison, analysis population, model and handling of repeated measures. Those details, and a p-value for the primary endpoint, are not reported in the registry record.

The registry’s sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between arms and a normal approximation. The intended effect to detect is described as a stated fraction of the observed effect. These are characteristics of an illustration, not evidence that the trial was designed with that justification or that it had a particular observed power. The registry record does not report the trial’s own sample-size justification. Planning calculations based on an observed effect should be read as hypothetical planning aids rather than as proof that a study could or could not detect a clinically relevant effect.

Over-dispersion is a general statistical concern when data vary more than a model assumes. If the model understates variability, its standard errors may be too small and its intervals too narrow. That concept is not identified as a specific issue in this trial, and the registry does not report a model assessment that would allow it to be evaluated.

Finally, analysis populations and missing-data procedures matter because exclusions or incomplete measurements can affect the comparison. The record does not describe an intention-to-treat population, a per-protocol population, missing-outcome handling or sensitivity analyses. Those features cannot be reconstructed from the design labels or the endpoint schedule.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary glucagon outcome and average blood glucose levels as a secondary outcome. It also gives the primary outcome at basal, euglycemia at 30 minutes and hypoglycemia at 105-120 minutes, with measurements described every 20 minutes during the 120 minute session. Testing several outcomes, stages or time points can raise a multiplicity issue: when many comparisons are examined, the chance of at least one apparently notable result may increase. An analysis plan may address this through prespecification, adjustment or a hierarchy of outcomes. The registry record does not report a multiplicity strategy or identify which time-point comparison was the primary statistical contrast.

The record states that the primary endpoint has several categories or time points and was not reduced to one comparison. That means a single headline comparison cannot be reconstructed from the registry entry. The numerical values and inferential results for those categories are not reported in the registry record, so it is not possible to assess whether any adjustment was applied or how multiple observations were interpreted.

Missing-data handling is also not reported in the registry record. There is no description of the number of participants contributing glucagon measurements at each stage, the reasons for any missing measurements, or whether imputation or sensitivity analyses were used. An endpoint schedule does not establish that every planned measurement was observed for every participant.

The analysis populations are not described. The registry does not state whether results were based on all randomized participants, participants who completed both conditions, or another defined group. It also does not report exclusions, adherence criteria or how crossover sequences were represented in analysis. These gaps limit assessment of how complete the analysis was and how closely the reported results, if available, would correspond to the randomized comparison.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists four safety groups: Control: Placebo, Control: Formoterol, Type 1 Diabetics: Placebo and Type 1 Diabetics: Formoterol. Each group lists seven participants at risk for serious adverse events, and zero participants affected by a serious adverse event. No top serious adverse-event terms are listed. These are counts in the registry’s safety presentation; they do not establish that no unlisted or unreported event occurred.

For other adverse events, the listed counts affected are two in Control: Placebo, three in Control: Formoterol, zero in Type 1 Diabetics: Placebo and two in Type 1 Diabetics: Formoterol. These counts should be interpreted with the group labels and denominators, not as a direct comparison adjusted for the crossover design. The record does not give event-level details or explain whether counts refer to participants with at least one event or to total events beyond the field’s affected-count label.

Deaths are recorded as null for the listed groups. A null entry is not the same as a reported count of zero; deaths are not reported in the registry record. Safety figures are descriptive and do not replace the missing numerical primary endpoint results or establish a general safety conclusion.

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

The record documents a trial intended to study whether inhaled formoterol changes the counterregulatory hormonal response during hypoglycemia in type 1 diabetes. It specifies glucagon concentration as the primary endpoint and describes repeated measurements across basal, euglycemia and hypoglycemia stages. It also identifies placebo as the comparator and describes a randomized, double-masked crossover design.

Those design and endpoint details explain the question being asked, but they do not answer it. Numerical glucagon results, a treatment contrast, an uncertainty interval and a p-value are not reported in the registry record. Therefore, the posted information does not establish the direction or size of any difference, how precisely it was estimated, or whether the results were compatible with no difference. The trial’s completed status is not an outcome finding.

The registry’s safety counts show zero serious adverse events among seven participants at risk in each listed group. Other adverse-event counts are also listed, while death counts are null. These safety entries are limited descriptive information and cannot demonstrate that the intervention is beneficial, ineffective or free of risk. They also do not provide a substitute for a complete account of event types, timing or severity.

The study enrollment was 14, and the registry describes both participants with type 1 diabetes and healthy volunteers. The relationship between these participant descriptions and the pooled placebo and control outcome summaries is not fully explained. This further limits interpretation of the intended comparison. The record does not report the analysis population, missing-data procedures or methods for handling the repeated measurements and crossover sequence.

The defensible conclusion is about the scope of the record: it identifies a small completed study and a biologically focused endpoint, but the numerical primary findings needed to evaluate the stated question are not reported in the registry record. No claim about treatment effect or clinical benefit follows from the aim alone.

13. Why This Trial Matters Statistically

This trial raises statistical issues that are common in studies with repeated physiological measurements and crossover allocation. The crossover model can support within-participant comparisons, but sound interpretation depends on the sequence, treatment-period structure and analysis of possible period or carryover effects. The registry record does not report those details, making the design label informative but insufficient to reconstruct the analysis.

The primary measure is recorded repeatedly during a defined session and is highlighted at distinct physiological stages. Such data contain both stage-specific information and within-participant dependence. A clear analysis must specify whether the question concerns a particular stage, a change from basal levels, or a pattern across time. The registry describes multiple stages but says the outcome was not reduced to a single comparison, and it does not report numerical estimates. This illustrates why endpoint definitions and analysis plans need to be read together.

The trial also includes descriptions of participants with type 1 diabetes and healthy volunteers, while the primary outcome summary refers to placebo and control. Clear labels and an explicit account of which population contributes to each comparison are important for interpreting pooled data. The relationship among those groups is not fully set out in the registry record.

Finally, the absence of numerical outcome results sharply limits what can be learned from the posted entry. Design information can show how a study was organized, and safety counts can describe reported events, but neither can replace effect estimates and uncertainty. The case highlights the distinction between a well-defined research question and an assessable statistical result.

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 main trial-specific limitation for interpretation is that numerical glucagon results are not reported in the registry record. Although the endpoint, unit, summary measure and measurement schedule are described, the means, standard errors and treatment comparison are absent. The record therefore does not permit assessment of the observed response or its precision.

The endpoint is described across several stages and time points, and the registry notes that it was not reduced to one comparison. Without a stated primary contrast or a reported approach to multiplicity, it is unclear which part of the repeated measurement profile was intended to carry the principal inferential claim. The analytical method for correlated measurements is not reported.

The registry identifies randomization, double masking and crossover allocation, but does not report treatment sequence, period structure, washout procedures or methods addressing period and carryover effects. It also does not describe the analysis population, missing-data handling, exclusions, adherence criteria or sensitivity analyses. The completion status and scheduled measurements do not establish that all participants contributed complete data.

The participant descriptions and outcome labels are not fully reconciled: the record names type 1 diabetes and healthy volunteers, while the endpoint description refers to placebo and control pooling regardless of randomization order. The registry does not explain how those groups map to the primary comparison.

Enrollment was 14, and the safety listing shows seven participants at risk per group. These counts provide context but do not resolve the missing outcome information. The record does not report the trial’s sample-size justification, so the enrollment figure alone cannot establish the study’s intended precision or ability to detect a relevant effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of Formoterol on the Counterregulatory Hormonal Response to Hypoglycemia in Type 1 Diabetes. — NCT01194479.
• Registry record last updated 2016-03-29; status last verified 2016-02.
• Results first posted 2016-03-29.
• 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

NCT01194479 is a completed randomized, double-masked crossover study sponsored by Yale University. Enrollment was 14; the recorded start was 2010-08 and primary completion was 2014-08. The registry lists phase NA and describes Formoterol and Placebo as the intervention conditions.

The study concerns the effect of inhaled formoterol on recovery from hypoglycemia and the hormonal response in type 1 diabetes. Its primary outcome is mean glucagon in pg/mL, with standard error specified as the dispersion measure. The record describes measurements during a 120 minute session, including basal, euglycemia at 30 minutes and hypoglycemia at 105-120 minutes. Average blood glucose levels are listed as a secondary outcome.

Numerical primary outcome findings and the analysis methods are not reported in the registry record. Safety listings show zero serious adverse events among seven participants at risk in each listed group; other adverse-event counts are also recorded, while death counts are null.