Safety Study of Sublingual Immunotherapy Tablets of House Dust Mite Allergen Extracts in Adolescents: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of Sublingual Immunotherapy Tablets of House Dust Mite Allergen Extracts in Adolescents (NCT01919554), a randomized phase 1 study. The primary outcome is Safety and Tolerability Evaluated on Treatment Emergent Adverse Events.

2. Clinical Question

The study concerns short-term tolerability in the stated adolescent population. It does not directly answer questions about longer-term exposure, other populations, or outcomes beyond those listed in the registry record. The results describe the number of participants with at least one event, rather than the total number of events or their severity distribution. Further details about the types of non-serious events are not reported in the registry record.

3. Trial Design

This was a phase 1, randomized, quadruple-masked, parallel study. The registry record lists an enrollment of 37 and identifies the sponsor as Stallergenes Greer. The study started in 2013-07, had primary completion in 2013-09, and is recorded as completed. Its stated purpose was to investigate the safety and tolerability of different doses of sublingual house dust mite allergen extract tablets in adolescents with house dust mite-associated allergic rhinitis.

Participants were assigned to one of three active dose groups or a placebo group. The posted primary outcome lists 9 participants in the 500 IR group, 9 in the 1000 IR group, 9 in the 1500 IR group, and 10 in the placebo group. These are the group sizes reported for that outcome. The record does not describe the randomization sequence, allocation concealment, or the roles covered by quadruple masking.

The primary endpoint covered 10 dosing treatment days. The analysis population was the Safety Set, defined as all patients who received at least one dose of treatment, including patients who did not complete the study. The registry record does not report the number screened, reasons for nonparticipation, treatment adherence, or the number who discontinued. It also does not report a protocol-level sample-size justification or planned statistical analysis details beyond what can be inferred from the posted outcome information.

The registry record lists two secondary outcomes: treatment-emergent serious adverse events and adverse events leading to study withdrawal. The reported primary result is a count of participants with at least one treatment-emergent adverse event. The study design supports a descriptive account of events by group; the record does not include estimates or tests for between-group differences.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Set: All patients who received at least one dose of treatment including those who did not complete the study were included in the Safety Set.

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: Safety Set: All patients who received at least one dose of treatment including those who did not complete the study were included in the Safety Set.

6. Primary Endpoint

The registry lists the primary outcome as Safety and Tolerability Evaluated on Treatment Emergent Adverse Events, measured over 10 dosing treatment days.

The primary endpoint is the number of participants who reported at least one treatment-emergent adverse event (TEAE) during 10 dosing treatment days. A participant is counted as having the endpoint if at least one qualifying event was reported; the measure does not count how many events that participant experienced. The registry record defines the analysis population as the Safety Set: all patients who received at least one dose, including those who did not complete the study.

Safety outcomes are used to describe events that occur during or after exposure to a study treatment and to identify patterns that may warrant closer assessment. A count of participants with any TEAE gives a broad summary of how many people experienced an event, but it does not by itself show the event's seriousness, duration, cause, or clinical importance. Nor does it establish that treatment caused an event. The registry record does not provide the individual non-serious event terms in the information reported for this outcome.

The endpoint is binary at the participant level: each person either had at least one TEAE or did not. The posted outcome reports counts and group sizes, without confidence intervals or a reported statistical comparison. As a result, the values are best read as descriptive counts from this study rather than as precise estimates of comparative risk.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of endpoint is reported?

The primary endpoint is binary at the participant level: the outcome records whether a participant experienced at least one TEAE during the specified treatment period. The posted values are counts of participants with an event, alongside the group sizes. Such outcomes are often analyzed by comparing proportions, because each participant contributes an event status rather than a continuous measurement. No proportions need to be calculated to interpret the reported counts, and no comparative estimate is reported in the registry record.

A count is easy to understand but does not communicate the precision of an estimate on its own. A confidence interval, when reported, describes a range of values compatible with the data under the analysis assumptions. It is useful for assessing how uncertain an estimate is, particularly when group sizes are small. Confidence intervals for this endpoint are not reported in the registry record. Without them, the counts should be treated as descriptive observations, not precise estimates of event frequency in a wider population.

What does randomization contribute?

Random assignment is intended to make treatment groups comparable on average with respect to factors present before treatment. It does not ensure that small groups will be identical in every characteristic, and it does not remove uncertainty from outcome comparisons. The record identifies the study as randomized but does not report the sequence-generation or allocation-concealment methods. It also does not provide participant characteristics by group, so the balance of those characteristics cannot be assessed from the posted information.

The study is described as quadruple-masked, but the registry record does not specify which roles were masked or how masking was maintained. Masking can reduce the chance that expectations influence treatment delivery, event reporting, or assessment. The reported designation alone does not show whether masking remained effective throughout the study.

Why does the Safety Set matter?

The defined analysis population includes all patients who received at least one dose, including those who did not complete the study. This is an exposure-based safety population: it focuses on people who were exposed to study treatment. The record does not state whether all randomized participants received treatment, how many did not complete the study, or how missing endpoint information was handled. Those details affect how fully the counts represent the randomized groups and cannot be inferred from the endpoint counts.

For a binary safety outcome, the count of participants with at least one event is different from the total number of events. A person with several events still contributes once to this particular endpoint. The outcome therefore summarizes how many participants were affected at least once, but it cannot describe recurrent events or event burden. The registry record does not give the event-level detail needed to assess those features for non-serious TEAEs.

What can be concluded without comparative tests?

The posted results give a count and group size for each arm, but no two-arm estimates or tests. A statistical comparison would ordinarily quantify the difference between groups and its uncertainty, subject to a specified analysis method. A p-value, when used, addresses how compatible the observed data are with a null hypothesis under the method's assumptions; it is not a measure of effect size or clinical importance. No p-value or confidence interval for a between-group comparison is reported in the registry record. The record notes that values are missing or not estimable for a two-arm comparison, so no comparative result should be reconstructed as if it were the sponsor's analysis.

In general, small samples can produce imprecise estimates for binary outcomes because each participant's event status has substantial influence on the group count. This is a general statistical consideration, not a separately reported trial finding. It reinforces why the observed counts should not be treated as stable estimates of what would occur in a broader population.

How should the planning illustrations be understood?

The record describes planning illustrations computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. Such calculations are hypothetical planning exercises, not outcomes observed in the trial and not evidence that the trial had a particular probability of detecting an effect. They are not the study's own design justification. The registry record does not report a protocol sample-size justification, and no planning sample-size values are reported in the information available for these results.

For this binary endpoint, a planning illustration expressed as participants per arm would depend on the assumed event rates, the chosen effect to detect, and the statistical assumptions. A normal approximation is a simplifying method for estimating the distribution of a statistic; with small group sizes, the accuracy of approximations can be a concern in general. The record does not provide enough detail to independently assess the calculations or substitute a different method. These illustrations should therefore be understood only as planning scenarios, not as observed power or a retrospective test of whether the trial was large enough.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("500 IR", "1000 IR", "1500 IR", "Placebo")
n      <- c(9, 9, 9, 10)
events <- c(4, 6, 9, 4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  500 IR  9  4  44.4  13.7  78.8  18.9  73.3  18.7  73.8
ARM  1000 IR  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8
ARM  1500 IR  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7
ARM  Placebo  10  4  40.0  12.2  73.8  16.8  68.7  16.7  69.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary safety outcome and two secondary outcomes: treatment-emergent serious adverse events and adverse events leading to study withdrawal. It does not report a multiplicity strategy, such as a hierarchy for testing outcomes or an adjustment for multiple comparisons. No inferential results for these outcomes are posted. Without a stated strategy and the corresponding results, the record does not support claims based on a family of statistical tests.

Missing-data handling is not reported in the registry record. The primary analysis population is the Safety Set, defined as patients who received at least one dose, including those who did not complete the study. That definition clarifies who is eligible for the safety summary, but it does not explain what happened if a participant's TEAE status was unknown, if follow-up was incomplete, or if a participant withdrew before the treatment period ended. Reasons for withdrawal and the completeness of event ascertainment are also not reported.

The registry record does not provide a participant flow account or an explicit intention-to-treat analysis. The primary endpoint counts and group sizes are posted for the Safety Set; they should not be assumed to represent every randomized participant unless that is documented. The record also does not report imputation or sensitivity analyses for missing outcomes. Consequently, the possible influence of missing information cannot be evaluated from the posted results.

These reporting gaps matter because missingness and multiple testing can affect how results are interpreted. They do not demonstrate that the analyses were improperly conducted; the relevant procedures are simply not reported in the registry record. No assumptions about them should be made.

12. 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 serious adverse event figures report 0 affected participants among 9 at risk in the 500 IR group, 0 among 9 in the 1000 IR group, 0 among 9 in the 1500 IR group, and 0 among 10 in the placebo group. These are counts during the reported safety observation, not proof that serious events could not occur. In small groups, observing no events still leaves uncertainty about the underlying event frequency.

The registry record lists treatment-emergent serious adverse events as a secondary outcome. The counts report no serious adverse events in the groups during the recorded period. Deaths are not reported in the registry record. No serious adverse event terms are listed, and the registry record does not provide further detail about event definitions, follow-up beyond the treatment period, or attribution to study treatment.

Serious adverse events and all TEAEs are not interchangeable summaries. The primary TEAE counts include participants with at least one treatment-emergent adverse event, while the serious-event figures concern the serious subset. The primary outcome counts were 4, 6, 9, and 4 participants in the 500 IR, 1000 IR, 1500 IR, and placebo groups, respectively. These different summaries answer different safety questions and should be interpreted within the short observation period.

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

The posted results establish that participants in each study group were assessed for whether they reported at least one TEAE during 10 dosing treatment days. The counts were 4 of 9 for 500 IR, 6 of 9 for 1000 IR, 9 of 9 for 1500 IR, and 4 of 10 for placebo. The serious adverse event counts were 0 in each group. These are observations from a phase 1 study with an enrollment of 37, not precise estimates for a broader population.

The results do not establish that any dose caused an event or that the observed counts represent a treatment effect. They do not show whether group differences are statistically distinguishable, because the registry record does not report inferential comparisons, confidence intervals, or p-values. They also do not indicate the severity or specific types of the non-serious events. The serious-event counts do not establish that serious events are impossible; they describe what was reported in these groups during the study record's observation.

The study was designed to investigate safety and tolerability in adolescents with house dust mite-associated allergic rhinitis, with a placebo group and three active dose groups. Its results do not answer questions about longer-term safety, efficacy, or outcomes in populations not described by the registry record. The record does not report missing-data methods, detailed participant flow, or a protocol sample-size justification, limiting further assessment of how complete and generalizable the results are.

Accordingly, the most defensible reading is descriptive: the registry record reports the number of participants with at least one TEAE and the number with serious adverse events in each group. It does not provide a basis for a comparative or causal conclusion.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how safety summaries can be useful while remaining limited. A participant-level count of people with at least one event is straightforward to interpret, and the registry record presents it separately for three dose groups and placebo. Seeing the group sizes alongside the counts is essential: the same count can convey different information depending on how many people were observed.

The design also makes clear why descriptive patterns should not be mistaken for inferential evidence. The TEAE counts differ across arms, but the groups are small and no comparative estimates or uncertainty intervals are reported. Randomization supports a planned comparison, but it does not make an observed count difference conclusive. Statistical interpretation depends on both the effect estimate and its uncertainty, neither of which is posted for a two-arm comparison.

The distinction between any TEAE and a serious adverse event is another useful statistical lesson. The primary endpoint records whether a participant had at least one event, while the serious-event summary concerns a subset of events with a different level of severity. Neither summary alone provides a complete account of event types, repeated events, duration, or attribution.

Finally, this study illustrates the importance of registry reporting for analysis populations, missing outcomes, and planning assumptions. The Safety Set is defined, but missing-data handling and a protocol-level sample-size justification are not reported. Planning illustrations based on an observed effect are separate from the study's original design and cannot be treated as observed power. These distinctions help keep a small safety study's descriptive results in their proper statistical scope.

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.

The most direct limitation is the small group size: the primary outcome lists 9 participants in each active group and 10 in placebo. Counts from groups of this size provide limited precision, and a small number of participants can materially change the observed pattern. The registry record does not report confidence intervals to quantify that uncertainty.

The observation period for the primary endpoint was 10 dosing treatment days. These results therefore do not characterize events after that period or longer-term safety. The primary outcome collapses all qualifying events into whether a participant experienced at least one; details about the specific non-serious event terms, severity, duration, recurrence, and treatment attribution are not reported in the registry record.

The registry record does not report two-arm comparisons, p-values, confidence intervals, or a statistical analysis plan. Randomization and quadruple masking are stated, but methods for sequence generation, allocation concealment, and the roles masked are not reported. The record also does not provide participant characteristics by arm, a detailed participant flow, reasons for study withdrawal, or treatment adherence.

Although the Safety Set is defined, handling of missing endpoint information and any sensitivity analyses are not reported in the registry record. The sample-size justification for the original study is also not reported. Planning illustrations based on an observed effect are not a substitute for that justification and should not be interpreted as observed power. These reporting limitations restrict assessment of precision, completeness, and the strength of any comparative interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety Study of Sublingual Immunotherapy Tablets of House Dust Mite Allergen Extracts in Adolescents — NCT01919554.
• Registry record last updated 2025-01-17; status last verified 2015-12.
• Results first posted 2025-01-17.
• 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 a completed phase 1 randomized, quadruple-masked, parallel study of sublingual house dust mite allergen extract tablets in adolescents with house dust mite-associated allergic rhinitis. Enrollment was 37; the study started in 2013-07 and had primary completion in 2013-09. The active groups were 500 IR, 1000 IR, and 1500 IR, with placebo as control.

The primary outcome was the number of Safety Set participants with at least one TEAE during 10 dosing treatment days. The posted counts were 4 of 9, 6 of 9, 9 of 9, and 4 of 10 for the active groups and placebo, respectively. Serious adverse events were reported for 0 participants in each group. Two secondary outcomes are listed, but inferential comparisons, missing-data methods, and a protocol sample-size justification are not reported in the registry record.