Hyaluronidase Effect on Infusion Set Life: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Hyaluronidase Effect on Infusion Set Life (NCT02199028), a randomized phase 1 study. The primary outcome is Duration of Insulin Infusion Set Wear as a Measure of the Effect of Hyaluronidase Treatment.

2. Clinical Question

3. Trial Design

The registry identifies this as a randomized, open-label, crossover study in phase 1. The condition listed is type 1 diabetes mellitus, and the interventions are hyaluronidase and control. The record reports that 30 subjects enrolled and 28 completed all scheduled visits. The primary-outcome description states that 117 total weeks of infusion-set wear were available for analysis, consisting of 58 hyaluronidase weeks and 59 standard weeks.

A crossover design evaluates conditions within a sequence in which participants receive different treatments or conditions over time. In general, this can make within-participant comparisons possible, because each participant may contribute observations under more than one condition. The registry record identifies this trial as crossover, but details of how period, sequence, or within-participant correlation were handled in the primary analysis are not reported in the registry record. Those details matter because observations from the same participant may be related rather than independent.

The arm descriptions indicate two sequences: Hyaluronidase, Then Control, and Control, Then Hyaluronidase. They describe active-treatment weeks and control weeks, including hyaluronidase administration on specified wear days. Parts of the arm descriptions are incomplete in the registry record, so the full schedule and all administration details are not reported in the registry record. The registry reports that masking was none; participants and study personnel therefore were not described as masked to treatment assignment.

The registry lists a study start of 2014-07, primary completion of 2015-03, and status of completed. Stanford University is listed as sponsor. It identifies three outcome measures and lists two secondary outcomes: maximum glycemic excursion and pain tolerability of hyaluronidase injections. The original protocol's rationale for the sample size, the planned statistical model, and any prespecified interim analyses 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.

Week 1

Reasons for not completing this period:

Week 2

Week 3

Reasons for not completing this period:

Week 4

Analysis population for the primary outcome, as defined in the registry: Thirty subjects were enrolled in this study; 28 completed all scheduled visits. Therefore, 117 total weeks of infusion set wear were available for analysis including 58 hyaluronidase weeks and 59 standard weeks.

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: Subjects between 12-45 years (inclusive) with clinical diagnosis of type 1 diabetes for at least one year, using an insulin pump for at least 3 months, and with an A1C less than 10%. 30 total subjects across two sites were enrolled and randomized the first week to either be in the control or experimental arm.

6. Primary Endpoint

The registry lists the primary outcome as Duration of Insulin Infusion Set Wear as a Measure of the Effect of Hyaluronidase Treatment, measured over Up to 4 weeks.

The primary endpoint is duration of insulin infusion-set wear, expressed as days of wear. The registry describes the outcome as the average, or mean, number of days for each group and states that a longer period of wear was considered a better outcome. It identifies the measure as continuous and the summary statistic as a mean with standard deviation.

Wear duration is used to quantify how long an infusion set remains in use before it is removed or otherwise stops contributing wear time under the study's outcome definition. As a practical measure within this trial, it directly addresses the stated research aim: examining whether hyaluronidase changes the length of time an infusion set can be worn. The record's primary-outcome timeframe is up to 4 weeks.

The endpoint is a summary of duration, not a direct measure of all possible reasons for ending wear. The registry record does not report the operational criteria used to decide when a set had failed or when wear ended, nor does it explain whether different causes of stopping wear were treated differently. Those details would help assess how consistently the outcome was determined and how its meaning relates to the intended treatment effect.

The posted group summaries report mean wear of 5.7 days for hyaluronidase and 5.4 days for control. The reported standard deviations are 1.7 and 1.9 days, respectively. A mean difference summarizes the contrast between these group means, while the spread within each group indicates that individual wear durations varied around the group average. Neither summary alone describes the full distribution of wear times or explains why particular infusion sets stopped being worn.

7. Results Posted in the Registry

• Hyaluronidase: mean 5.70 versus 5.40 on control; difference 0.30 (95% CI -0.61 to 1.21), standardized effect d = 0.17; z-test p = 0.519.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean difference represent?

General statistical explanation: A mean difference subtracts the average in one condition from the average in another, using a stated direction for the comparison. It is expressed in the same units as the outcome. Here the outcome is days of infusion-set wear, the posted means are 5.7 days and 5.4 days, and the reported mean difference is 0.3 days, with the estimate favoring longer mean wear in the hyaluronidase condition. The difference is an estimate from the observed data; it is not a guarantee that every participant or wear episode experienced that change.

General statistical explanation: A mean compresses the observations into a single summary. It can be useful for comparing groups, but it does not show the full distribution, whether values cluster or are unevenly spread, or whether a small number of unusually long or short durations influenced the average. The reported standard deviations provide a measure of spread around the means, but they do not replace inspection of the underlying observations.

What do standard deviations describe?

General statistical explanation: A standard deviation describes variability among observations around a mean. A larger standard deviation indicates more dispersion in the recorded values, while a smaller one indicates values that are more concentrated around the mean. The posted standard deviations are 1.7 days for hyaluronidase and 1.9 days for control. They describe observed variability, not the precision of the estimated difference. Precision is conveyed by the confidence interval for that difference.

General statistical explanation: A standard deviation and a standard error answer different questions. The standard deviation concerns variation among individual observations; the standard error concerns uncertainty in an estimate, such as a mean or mean difference. The registry lists standard deviations for the groups and also reports a confidence interval for the contrast. It does not describe in detail how the contrast's standard error was derived or whether the crossover structure informed that calculation.

How should the p-value be read?

General statistical explanation: A p-value describes how compatible the observed result, or a result more extreme under a specified test, is with a null hypothesis and the assumptions of that test. It is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of an effect. The reported unadjusted p-value is 0.519. Its interpretation depends on the analysis and assumptions used; details of the test and its treatment of the crossover design are not reported in the registry record.

General statistical explanation: A p-value does not by itself distinguish a truly absent effect from an estimate that is uncertain because the data are limited or variable. The estimate and its confidence interval should be considered together. In this trial, the estimated difference is 0.3 days, while the interval crosses zero. This combination reflects uncertainty about both the direction and magnitude of the underlying difference.

Why does the crossover structure matter?

General statistical explanation: In a crossover study, measurements made under different conditions for the same participant can be correlated. A method that accounts for this correlation may estimate uncertainty differently from a method that treats all observations as independent. Period and sequence can also matter if outcomes change over time or if the order of conditions affects observations. These are general features of crossover analysis; the registry record does not report the model or adjustment choices used for this primary comparison.

The primary-outcome description gives 58 hyaluronidase weeks and 59 standard weeks available for analysis. The posted group summaries list 30 observations per condition. The record does not make clear how the summary observation counts map to the weeks of wear or how those observations were paired or grouped by participant. It also does not report whether the comparison used participant-level summaries, wear-week observations, or another analytic unit. This limits the ability to reconstruct the analysis from the registry information alone.

What does an unadjusted comparison mean?

General statistical explanation: An unadjusted comparison reports a contrast without accounting for other variables or design features through an adjustment model. The word unadjusted describes the reported p-value; it does not establish which factors were or were not considered in every other aspect of the analysis. The record does not report a covariate-adjusted estimate, a detailed model specification, or a method for handling repeated observations. It is therefore best to identify the posted result as an unadjusted comparison and avoid attributing unreported modeling choices to it.

General statistical explanation: Randomization is intended to reduce systematic differences in treatment assignment, but it does not eliminate uncertainty or guarantee that every measured and unmeasured characteristic is balanced in a particular study. In a crossover design, participants serve in more than one condition over time, but the analysis still needs to reflect the dependence of observations and the design's timing. The registry identifies randomization and crossover; it does not report enough analysis detail to assess those features fully.

What can the summaries establish?

The reported summaries establish what the registry posts: mean wear of 5.7 days in the hyaluronidase group and 5.4 days in the control group, a mean difference of 0.3 days, standard deviations of 1.7 and 1.9 days, and an unadjusted p-value of 0.519. The confidence interval crosses zero. These values describe the estimated contrast and its uncertainty, but they do not establish a causal effect beyond the assumptions of the trial design and analysis.

General statistical explanation: Statistical significance, effect magnitude, precision, and practical importance are related but distinct. A small p-value is not a measure of clinical importance; a non-significant p-value is not proof of no effect; and a point estimate alone does not show how uncertain the result is. Interpretation should therefore consider the size of the estimated difference, the interval around it, the outcome's relevance, the design, and the quality and completeness of the reported analysis. For this trial, the registry record does not report a threshold for a meaningful difference in wear duration, so the practical importance of a difference of 0.3 days cannot be judged from the record alone.

10. Confidence Intervals and Precision

The estimated mean difference in insulin infusion-set wear is 0.3 days, favoring longer mean wear with hyaluronidase. Its confidence interval extends from a negative value to a positive value and therefore includes zero. The interval's span indicates that the estimate is not precise enough to establish the direction of the difference: the data are compatible with a lower mean under hyaluronidase as well as a higher mean.

General statistical explanation: A confidence interval gives a range of estimates that are reasonably compatible with the data under the method's assumptions. It reflects sampling uncertainty, not the range of individual outcomes and not a guarantee that the true value lies within the interval. A narrow interval indicates greater precision; a wide interval indicates less precision. The interval should be considered alongside the estimated difference and the study's design and analysis.

The registry reports group standard deviations of 1.7 days for hyaluronidase and 1.9 days for control. These values describe variation in wear duration, whereas the confidence interval concerns uncertainty in the mean difference. The listed group summaries report 30 observations in each condition, while the primary-outcome description reports 117 weeks available for analysis and 28 participants completing all scheduled visits. The relationship among these counts is not reported in the registry record, which complicates assessment of how much information supports the estimate.

The unadjusted p-value is 0.519, consistent with the interval's inclusion of zero. Neither the p-value nor the interval alone indicates whether a difference would be important in practice. A threshold for a meaningful change in days of wear is not reported in the registry record. The crossover analysis method and handling of within-participant dependence are also not reported, so the interval's precision should be understood in light of that missing methodological detail.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size display gives planning illustrations based on the observed effect, rather than the trial's original design assumptions. The figures are participants per arm, not total event counts. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect.

For planning for 100% of the observed effect, the display lists 567 participants per arm for 80% power and 759 participants per arm for 90% power. For planning for 75% of the observed effect, it lists 1,008 participants per arm for 80% power and 1,350 participants per arm for 90% power. For planning for 50% of the observed effect, it lists 2,268 participants per arm for 80% power and 3,036 participants per arm for 90% power.

In plain terms, the 80% power column gives the illustrated number of participants per arm for a design with an 80% chance of detecting the chosen effect under the stated assumptions, if that effect is real and the assumptions hold. The 90% power column uses a higher target chance of detection and therefore requires more participants in these illustrations. Smaller target effects need more participants because they are harder to distinguish from random variation.

These figures are planning illustrations, not observed power and not evidence about the study's original sample-size rationale. The trial's own design assumptions and sample-size justification are not reported in the registry record. The displayed curve should be read in the same planning context: it represents how the illustrative participant requirement changes as the target effect changes, under the stated assumptions. The calculation does not establish that a future trial would achieve the listed power if its design, outcome variability, analysis, or other assumptions differed.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.300; pooled standard deviation σ = 1.803.
2. n = 2 × (1.96 + 0.842)² × 1.803² / 0.300² = 566.9, rounded up to 567 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.3                      # observed difference in means
sigma <- 1.80277563773199                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2199028)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 567 (80% power), 759 (90% power)
 75% of observed effect: n per arm = 1,008 (80% power), 1,350 (90% power)
 50% of observed effect: n per arm = 2,268 (80% power), 3,036 (90% power)
power.t.test: 567.8 
Simulated power at n = 567 per arm: 0.798 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists two secondary outcomes: maximum glycemic excursion and pain tolerability of hyaluronidase injections. It reports three outcome measures in total, but the posted results described for this analysis include the primary endpoint rather than results for those secondary outcomes. Whether the secondary outcomes were collected, how they were analyzed, and why their results are absent are not reported in the registry record.

Multiplicity arises when several outcomes, comparisons, or analyses are examined. General statistical explanation: When many tests are conducted, the chance of obtaining at least one apparently unusual result by chance can increase. Statistical plans may address this through prespecified priorities or adjustment procedures. Whether this trial had a prespecified multiplicity strategy, and whether any adjustment was used, are not reported in the registry record. The primary result should not be treated as if it were automatically adjusted for the other listed outcomes.

The registry lists zero analyses. This does not explain what statistical procedures were actually conducted or whether analyses were performed but not entered in the record. A detailed analysis plan, including the primary test, any covariate adjustment, handling of crossover periods, and definitions of analysis populations, is not reported in the registry record. Interim analyses and stopping rules are also not reported in the registry record.

The primary-outcome text states that 30 subjects enrolled and 28 completed all scheduled visits, and that 117 weeks of wear were available for analysis. The registry does not explain how incomplete visits or unavailable wear periods were handled, whether missing observations were imputed, or whether exclusions were applied. The definition of the population included in the primary analysis is not reported in the registry record beyond the statement about available weeks.

General statistical explanation: Missing outcomes can affect an estimate if the chance that a value is missing relates to the value itself or to treatment and outcome characteristics. The consequences depend on why data are missing and on the analysis method. The record does not report reasons for missing visits or wear observations, so the direction or extent of any effect on the estimate cannot be determined. The crossover structure also makes the handling of incomplete sequences potentially relevant, but the record does not state whether participants with incomplete data contributed partial observations.

14. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry's adverse-event summary reports zero serious adverse events affecting participants in the hyaluronidase-week group and zero in the control-week group. The listed numbers at risk are 30 for each group. These are the serious-event figures recorded for the reported groups; they do not by themselves provide a complete account of all safety outcomes or establish that no serious events occurred outside the registry's reported observation and classification.

The record also lists other adverse events affecting 16 participants during hyaluronidase weeks and 17 during control weeks, with 30 at risk in each group. These are counts of participants affected in the respective groups, not rates calculated. The record does not provide event-level details in the listed summary, so the types, timing, severity, and relationship of those other events to treatment are not described in this account.

Death counts are not reported in the registry record. No top serious-event terms are listed. The registry information does not specify the safety observation period, event-collection procedures, or whether events could be counted in both conditions for the same participant. As a result, the group counts should be read as descriptive reports rather than as a standalone comparative safety analysis. No statistical test or adjusted comparison of adverse events is reported in the registry record.

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

The posted primary results show mean infusion-set wear of 5.7 days with hyaluronidase and 5.4 days with control. The estimated mean difference is 0.3 days, and the confidence interval includes both negative and positive values. The unadjusted p-value is 0.519. These findings describe an estimated difference with substantial uncertainty about its direction; they do not establish a clear separation between the conditions.

The result does not demonstrate equivalence, because the registry record does not report an equivalence margin or an analysis designed to establish equivalence. It also does not prove that there is no difference. A result with a confidence interval crossing zero can reflect no underlying difference, but it can also be compatible with differences in either direction. The degree to which those possibilities matter depends partly on what size of change in wear duration would be meaningful, and such a threshold is not reported in the registry record.

The observed group means are summaries of recorded wear duration. They do not tell readers why wear ended, whether all wear periods were observed under the same conditions, or how the incomplete visit information was handled. The record reports 28 participants completed all scheduled visits and 117 weeks of wear were available for analysis, but it does not fully explain how these observations relate to the group summary counts of 30 per condition.

The study is described as randomized and crossover, but the statistical model and handling of repeated observations are not reported in the registry record. The posted comparison should therefore be interpreted as a summary of the result rather than a complete account of every design feature that may affect uncertainty. Results for the listed secondary outcomes are not included in the registry record.

These data do not support medical advice or a treatment recommendation. They report one study's primary outcome and its uncertainty. They should not be generalized beyond the trial population, intervention schedule, outcome definition, and analysis information available in the registry record.

16. Why This Trial Matters Statistically

This trial raises a statistical issue that is important in clinical research: the design, data structure, and analysis need to be read together. The registry identifies a randomized crossover study, while the primary outcome is summarized as mean wear duration under hyaluronidase and control. Crossover data may include repeated observations from the same participant, so the way those observations are grouped and modeled can affect estimates of uncertainty. The record gives some information about available wear weeks but does not describe the analysis model or how within-participant dependence was handled.

The comparison also illustrates why the estimate, uncertainty, and p-value should be interpreted together. The mean difference is 0.3 days, but the confidence interval spans values on both sides of zero, and the unadjusted p-value is 0.519. Reporting only the difference might overstate certainty; reporting only the p-value might obscure the estimated magnitude and the range of effects compatible with the data. The interval is essential for understanding how inconclusive the estimate remains.

The distinction between participants and wear periods is relevant as well. The registry reports 30 enrolled, 28 completing all scheduled visits, 117 weeks available for analysis, and group summaries listing 30 observations per condition. It does not explain the relationship among these counts. Clear reporting of the analytic unit, missing observations, and analysis population would help readers assess the information supporting the comparison.

Finally, planning illustrations based on the observed effect are not a substitute for a trial's original design rationale. They can show how participant requirements change under stated assumptions, but the registry does not report the assumptions that guided the initial enrollment target. This distinction matters when readers use a result to understand future study planning.

17. 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 leaves important details of the primary analysis unspecified. Although it identifies the study as randomized and crossover, it does not report the statistical model, the treatment of within-participant correlation, or whether period and sequence were considered. The available summaries therefore do not permit a full appraisal of whether the posted uncertainty reflects the crossover structure.

The relationship among the reported counts is not explained. The record says 30 subjects enrolled, 28 completed all scheduled visits, and 117 total weeks were available for analysis, including 58 hyaluronidase weeks and 59 standard weeks. The posted group summaries list 30 observations in each condition. The registry does not identify the unit behind those summary counts or explain how the reported analysis population was formed.

The arm descriptions are incomplete in the registry record. They describe treatment sequences and some hyaluronidase administration details, but the full schedules and all procedural information are not reported in the registry record. The endpoint's operational definition, including criteria for ending wear, is also not reported. These omissions limit interpretation of exactly what each recorded duration represents.

Reasons for incomplete visits or unavailable wear observations, methods for handling missing data, and any exclusions from analysis are not reported in the registry record. Results for the two listed secondary outcomes are not included. The registry does not report a multiplicity strategy, the original sample-size justification, interim analyses, or a detailed statistical analysis plan. These gaps make it difficult to assess selective reporting, the intended analysis population, and the degree to which the posted analysis followed a prespecified plan.

The study is listed as phase 1, and its enrollment is 30. The registry record does not report a meaningful-difference threshold for wear duration. As a result, the practical importance of the estimated difference cannot be determined from the statistical summaries alone. The findings are specific to the recorded study conditions and should not be generalized beyond the information available in the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Hyaluronidase Effect on Infusion Set Life — NCT02199028.
• Registry record last updated 2019-10-11; status last verified 2019-09.
• Results first posted 2019-10-11.
• 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.

21. Record Summary

The registry record describes NCT02199028, titled “Hyaluronidase Effect on Infusion Set Life,” as a completed, randomized, unmasked, phase 1 crossover study sponsored by Stanford University. The listed condition is type 1 diabetes mellitus. The study enrolled 30 subjects, and 28 completed all scheduled visits. The primary-outcome timeframe was up to 4 weeks.

The primary endpoint was mean duration of insulin infusion-set wear in days. The posted mean was 5.7 days for hyaluronidase and 5.4 days for control, with a mean difference of 0.3 days and an unadjusted p-value of 0.519. The confidence interval crosses zero, leaving uncertainty about the direction of the difference. The registry also lists maximum glycemic excursion and pain tolerability of hyaluronidase injections as secondary outcomes.

The record reports zero serious adverse events affecting participants in either group and other adverse events affecting 16 participants during hyaluronidase weeks and 17 during control weeks. The crossover analysis details, missing-data methods, multiplicity strategy, and original sample-size rationale are not reported in the registry record.