IN Insulin in Type 1 Diabetes (T1D) Hypoglycemia Unawareness: Safety Only Phase: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for IN Insulin in Type 1 Diabetes (T1D) Hypoglycemia Unawareness: Safety Only Phase (NCT04028960), a randomized phase 2 study. The primary outcome is Percentage of Time With Dangerous Hypoglycemia.

2. Clinical Question

The registry describes a phase 2 study intended to assess how intranasal regular insulin affects the ability to feel low blood glucose, using continuous glucose monitoring to collect information. The listed primary endpoint is a CGM measure of time below a specified glucose threshold. It quantifies recorded exposure to low glucose rather than directly measuring a participant’s subjective awareness.

The clinical question is framed as a comparison of insulin with placebo in people with type 1 diabetes. The record identifies hypoglycemia awareness in the brief summary but hypoglycemia unawareness in the study title; the exact intended population wording is therefore not fully consistent. Eligibility criteria and further population characteristics are not reported in the registry record.

The primary endpoint timeframe is two treatment periods of 14-20 days. The registry record does not report an inferential estimate for the comparison, so the descriptive arm values alone do not establish whether the observed difference is attributable to treatment. The stated question and the available results should be kept distinct: the former describes the planned clinical comparison, while the latter provide only limited numerical summaries.

3. Trial Design

This was a randomized, triple-masked, crossover phase 2 study. The registry lists enrollment of 4 and status as terminated. It records a start date of 2019-10-23 and a primary completion date of 2020-04-08. The reason for termination is not reported in the registry record.

A crossover design means that treatment comparisons are made across treatment periods rather than by assigning separate groups of participants to receive only one treatment. In general, this design can allow each participant to contribute information under more than one condition. The registry labels the study as crossover and gives the primary endpoint timeframe as two 14-20 day treatment periods. The sequence assigned to participants, the timing of transitions, and any washout interval are not reported in the registry record.

Randomization is listed, but the randomization method and allocation sequence are not reported in the registry record. Triple masking is also listed; which people or roles were masked is not reported in the registry record. The arm descriptions identify placebo as no active drug and Humulin-R as insulin. Regular insulin by the intranasal route and the SipNose intranasal device are named among the interventions. The brief summary states that the study drug or placebo was delivered using an intranasal device.

The primary endpoint is a continuous measure: mean percentage of time below 54 mg/dL, calculated from real-time CGM. The record also lists secondary measures relating to time in glucose ranges, sensor wear, mean glucose, variability, and glucose management indicator. Although 8 secondary outcomes are posted and 9 outcome measures are listed, the number of analyses is 0. Analysis methods, treatment-sequence handling, and the analysis population are not reported in the registry record.

The small enrollment and crossover structure are important when reading the results. The posted summaries list 4 participants in each arm, but the registry record does not provide participant-level data or explain how the arm counts relate to the crossover analysis. It also does not report whether all enrolled participants completed both treatment periods.

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

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: Four subjects were enrolled in the study. Two subjects started the study in the placebo arm and the other two started the study in the Humulin-R arm. During the study, each participant crossed over to the opposite arm of the study so that each subject participated in both arms of the study.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Time With Dangerous Hypoglycemia, measured over Two 14-20 day treatment periods.

The primary endpoint is the percentage of time with dangerous hypoglycemia. The registry defines this using percent time below range, specifically CGM readings below 54 mg/dL, and identifies the measure as a mean with standard deviation. The stated timeframe is two 14-20 day treatment periods. This is a continuous endpoint: it summarizes the amount of monitored time spent below a glucose threshold rather than counting separate episodes.

Continuous glucose monitoring can capture glucose levels repeatedly during daily life, allowing a time-based summary of low glucose exposure. As a general statistical point, a threshold-based time measure is useful when the clinical question concerns how much monitored time is spent in a range of interest. It does not, by itself, describe symptoms or establish whether a participant recognized a low glucose event. In this study, the stated aim involves the ability to feel low blood sugar, whereas the primary endpoint measures CGM time below a threshold. Those concepts are related in the study rationale but are not identical measurements.

The posted mean is 0.57 for placebo and 0.77 for Humulin-R; the corresponding standard deviations are 0.73 and 1.08. These values are reported as percentages of time, but the registry record does not provide a confidence interval or a formal comparison estimate. The record also does not clarify the handling of sensor gaps or the calculation details beyond the stated CGM definition. These omissions limit how precisely the endpoint can be interpreted.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a continuous measure reported as a mean and standard deviation. The registry gives one mean and one standard deviation for each arm, along with 4 participants per arm. It does not post a comparison estimate for the primary endpoint. The statistical interpretation should therefore separate what is directly described by the arm summaries from what would require an analysis of the treatment contrast.

What does the mean describe?

The mean is the average value of the endpoint in the reported arm. Here, the endpoint is percentage of time with CGM glucose below 54 mg/dL over the stated treatment periods. The reported mean is 0.57 for placebo and 0.77 for Humulin-R. These summaries describe the observed arm values; they do not account for uncertainty in a treatment comparison or establish that treatment caused any difference.

As a general concept, a mean can be a useful summary of a continuous measure, but it may not show the distribution of individual observations. A few unusual values can influence a mean, and the mean alone does not show whether observations are clustered or widely dispersed. Individual participant results and distributional plots are not reported in the registry record.

What does the standard deviation describe?

The standard deviation summarizes how spread out the observations are around the mean. The posted values are 0.73 for placebo and 1.08 for Humulin-R. A standard deviation is not the same as a standard error and is not a confidence interval. It describes variability among observed values rather than the precision of an estimated treatment contrast.

As a general statistical concept, a confidence interval represents a range of estimates compatible with the data and the method used to calculate it. The registry record does not report a confidence interval for this endpoint. Without a comparison interval, readers cannot judge the precision of the treatment contrast from the posted arm summaries alone.

Why does crossover design matter?

The registry classifies the study as crossover. In a crossover study, the same participant may contribute observations under different treatment conditions. A statistical comparison can then make use of the pairing of measurements within participants. The difference between a participant’s measurements and the variation in those paired differences can be important for estimating the treatment contrast. Arm means and standard deviations do not show that pairing.

The sequence of treatment periods, washout details, and any adjustment for period or sequence effects are not reported in the registry record. As a general matter, measurements in a crossover study can be affected by the order or timing of treatment periods. The record does not say whether these issues were assessed or how they were handled. It is therefore not possible to infer the analysis model from the design label alone.

What does the missing comparison mean?

The registry indicates that values are missing or not estimable for a two-arm comparison of this continuous endpoint. No comparison estimate, p-value, or confidence interval is posted. The descriptive means can be quoted, but a new difference should not be calculated from them. Such a calculation would not recover a crossover analysis because the within-participant data and analysis method are unavailable.

As a general statistical point, an inferential comparison combines an estimated effect with a measure of uncertainty. A p-value addresses compatibility with a specified null model under the assumptions of a test; a confidence interval communicates a range of plausible effect estimates under its method. Neither is available for the primary comparison in the registry record. The reported arm summaries alone cannot substitute for either.

How should planning illustrations be understood?

Any sample-size illustrations based on an observed effect are planning calculations, not results from participants and not observed power. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. For non-time-to-event outcomes, the illustrations are expressed as participants per arm. These assumptions describe an illustration, not the original study design or a documented sample-size justification.

As a general concept, sample-size planning asks how much information might be needed to detect a chosen effect under specified assumptions. It does not show the probability that a completed study has demonstrated an effect, and it does not repair missing inferential results. The registry record does not report the original sample-size justification. The illustrations should therefore be treated as hypothetical planning context, not evidence about the reliability of the trial findings.

What does the secondary outcome listing add?

The registry lists secondary measures covering time between 70 and 180 mg/dL, time below 70 mg/dL, time above 180 mg/dL and 250 mg/dL, active sensor wear, mean glucose, coefficient of variation, and glucose management indicator. It reports 8 secondary outcomes and 9 outcome measures, with 0 analyses listed. The record does not report detailed results or analysis methods for these outcomes. Their presence identifies additional measures of interest, but it does not establish that each was analyzed or reported.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Placebo", "Humulin-R")
n   <- c(4, 4)
m   <- c(0.57, 0.77)
sp  <- c(0.73, 1.08)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  4  0.570  0.730  -0.592  1.732
CARM  Humulin-R  4  0.770  1.080  -0.949  2.489

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 secondary outcomes in addition to the primary endpoint and reports 9 outcome measures overall. It lists 0 analyses. A multiplicity strategy, such as an ordering of hypotheses, adjustment method, or distinction between confirmatory and exploratory outcomes, is not reported in the registry record. Without that information, the results cannot be interpreted as a documented family of confirmatory tests.

As a general statistical concept, testing several outcomes can increase the chance of finding at least one apparently notable result by chance if each is considered independently. Multiplicity procedures can address that concern, but the choice depends on the study’s analysis plan and objectives. The registry record does not report whether any such procedure was planned or used. No secondary-outcome inferential results are available in the record to evaluate.

Missing-data methods are also not reported in the registry record. The primary outcome depends on CGM monitoring, and the registry does not describe how sensor gaps, incomplete periods, or participants lacking usable measurements were handled. The number enrolled is 4, and 4 participants are listed for each arm, but completion and analysis-population details are not reported. The record does not state whether results were analyzed according to randomized assignment, among participants who completed treatment, or using another population definition.

As a general matter, missingness can affect a time-based CGM summary if the recorded periods do not represent the full intended observation period. The direction and extent of any such effect cannot be determined from the record. The registry’s note that a two-arm continuous-endpoint comparison was not estimable further limits interpretation. No assumptions about unreported missing data or analysis populations should be inferred.

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 serious adverse events for 4 participants at risk in each arm. There were 0 serious adverse events in the placebo group and 0 in the Humulin-R group. Deaths are reported as 0 in each group. No serious adverse event terms are listed.

For other adverse events, 3 participants are reported as affected among the 4 at risk in the placebo group, and 4 participants are reported as affected among the 4 at risk in the Humulin-R group. These are participant counts, not event rates adjusted for exposure time. The record does not provide event-level descriptions or the duration of safety observation for each participant.

As a general statistical point, observing no serious adverse events in a small group does not demonstrate that the risk is absent. Sparse safety counts provide limited information about uncommon events, and the registry does not report a comparative safety analysis. The other-adverse-event counts are descriptive and do not, by themselves, establish a treatment-related difference. The reason the study was terminated is not reported in the registry record, so termination should not be attributed to these safety figures.

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

The posted results establish that the registry contains descriptive primary-endpoint summaries for a small study: the mean percentage of time below 54 mg/dL is 0.57 for placebo and 0.77 for Humulin-R, with standard deviations of 0.73 and 1.08, respectively. The registry lists 4 participants in each arm. These values describe the recorded summaries, not a statistically established treatment effect.

The registry record does not report a formal two-arm estimate or its uncertainty. The means therefore cannot establish whether the observed ordering reflects a true treatment difference, random variation, period effects, incomplete monitoring, or other factors. In particular, because the design is crossover, the within-participant measurements and their relationship matter; those data are not reported in the registry record.

The outcome is time below a CGM threshold, not a direct measure of awareness. While the study rationale concerns the ability to feel low blood sugar, a CGM-based time percentage does not directly establish whether a participant noticed or recognized a low reading. The wording of the population also differs between the title and brief summary: one refers to unawareness and the other to awareness. The record does not resolve that distinction.

The record does not establish that the intervention is beneficial, harmful, or equivalent to placebo. It also does not establish the absence of rare safety risks. The listed safety counts are descriptive, and the study’s termination reason is not reported. The limited enrollment and the missing comparison estimate constrain what can be inferred from the outcome summaries.

As a general interpretation principle, the strength of a conclusion depends on both the estimated effect and the uncertainty around it, as well as the design and quality of the data. Here the registry provides arm-level descriptive values but not an inferential comparison. The appropriate reading is therefore narrow: these are the posted summaries for a terminated, randomized crossover study, and they do not settle the clinical question.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a crossover design with a very small enrollment and a continuous CGM endpoint. A crossover design can be efficient when participants contribute measurements under multiple treatment conditions, but the validity and precision of the comparison depend on paired observations and appropriate handling of treatment periods. The registry does not provide those analytical details, so the arm summaries cannot be used to reconstruct the intended comparison.

The primary measure is also a time-based endpoint. Such a measure depends on the duration and completeness of monitoring, as well as the threshold used to define the outcome. The registry specifies CGM time below 54 mg/dL and a timeframe of two 14-20 day treatment periods, but it does not describe sensor-gap handling or completeness rules. Those choices can matter when the monitored time is the outcome itself.

The distinction between a physiological measurement and a subjective construct is important. The study rationale concerns hypoglycemia awareness, while the primary endpoint captures time below a glucose threshold. The endpoint can describe recorded low-glucose exposure, but it is not itself a direct report of recognition or awareness. The title and brief-summary descriptions of the target population also differ.

Finally, the registry posts arm means and standard deviations but no comparison estimate for the primary endpoint. This illustrates why descriptive results and inferential results serve different purposes. A pair of arm summaries gives some information about observed values; a treatment comparison requires an estimate of contrast and its uncertainty, especially in a crossover study. The record’s limitations make restraint in interpretation essential.

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 limitations restrict interpretation. The registry reports enrollment of 4 and lists 4 participants in each arm, but it does not report how many completed both treatment periods or contributed usable CGM data. It also does not describe the analysis population, participant flow, or whether any outcome data were missing.

The trial is identified as crossover, but treatment sequence, period-specific results, washout details, and methods for handling period or sequence effects are not reported in the registry record. These details are important because a crossover comparison depends on observations within participants. The posted arm summaries do not provide the paired data needed to assess that comparison.

The registry does not report a primary-endpoint comparison estimate, confidence interval, or p-value, and notes that a two-arm continuous-endpoint comparison was not estimable. It does not report the original sample-size justification or the reason for termination. The planning assumptions described for sample-size illustrations should not be mistaken for the original design rationale.

The record lists secondary outcomes but does not report detailed results or analysis methods for them. It also does not report a multiplicity plan, missing-data procedures, or rules for CGM sensor gaps. These omissions leave uncertainty about how the planned measures were analyzed and how complete monitoring contributed to the endpoint.

Finally, the study title and brief summary differ in their wording about hypoglycemia awareness, and the primary endpoint is a CGM threshold measure rather than a direct report of awareness. The registry record does not resolve the population wording or provide additional information linking the primary measure to subjective recognition. These limitations do not negate the posted summaries, but they narrow the claims those summaries can support.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: IN Insulin in Type 1 Diabetes (T1D) Hypoglycemia Unawareness: Safety Only Phase — NCT04028960.
• Registry record last updated 2021-05-18; status last verified 2020-05.
• Results first posted 2021-05-18.
• 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

The registry record describes NCT04028960, a randomized, triple-masked, crossover phase 2 study sponsored by HealthPartners Institute. It lists enrollment of 4 and status as terminated. The intervention is intranasal regular insulin (Humulin-R), with placebo as the comparator; the SipNose intranasal device is also listed. The primary endpoint is mean percentage of CGM time below 54 mg/dL during two 14-20 day treatment periods.

The posted primary summaries are a mean of 0.57 with standard deviation 0.73 for placebo and a mean of 0.77 with standard deviation 1.08 for Humulin-R; 4 participants are listed in each arm. A two-arm comparison estimate is not reported. The record lists 8 secondary outcomes and 9 outcome measures, with 0 analyses. Serious adverse events and deaths are reported as 0 in each arm. The reason for termination, analysis methods, and missing-data procedures are not reported in the registry record.