Safety of Lactobacillus Reuteri in Healthy Children Aged 2-24 Months: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Lactobacillus Reuteri in Healthy Children Aged 2-24 Months (NCT02460575), a randomized phase 1 study. The primary outcome is Number of Participants With Positive Blood Culture for L. Reuteri.

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel-group Phase I trial sponsored by Tulane University School of Medicine. The registry title identifies the population as healthy children aged 2-24 months, and the condition is listed as Healthy. The planned enrollment was 60. The brief summary says children would receive study product at a treatment-to-placebo ratio of 2:1. The posted arm counts are 40 for Lactobacillus and 20 for placebo.

The active product was Lactobacillus reuteri 17938, suspended in sunflower oil, medium chain triglyceride oil, and silicone dioxide. The placebo contained sunflower oil, medium chain triglyceride oil, and silicon dioxide, with zero CFU of L. reuteri per 5 drops. The summary describes administration for five successive days and follow-up for 3 months for safety outcomes. For the primary endpoint, the recorded timeframe says participants were followed for an average of 36 days. These descriptions refer to the study follow-up and the endpoint timeframe as recorded; the registry does not explain the difference between them.

The record lists the study start as 2019-01-09, primary completion as 2019-12-29, and status as completed. The record does not report the randomization sequence method, allocation concealment procedures, masking roles, or details of trial conduct. It also does not report recruitment locations, participant flow, withdrawals, or adherence. Those omissions limit how fully the design and the completeness of outcome ascertainment can be assessed from the registry record 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

Reasons for not completing this period:

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 Number of Participants With Positive Blood Culture for L. Reuteri, measured over Participants are followed for an average of 36 days.

The primary endpoint was the number of participants with a positive blood culture for L. reuteri. This is a participant-level count: a participant either had a positive culture recorded or did not. It is therefore a binary safety outcome summarized as counts in the two arms, rather than a measurement of the amount of bacteria or a time-to-event measure. The endpoint timeframe says participants were followed for an average of 36 days.

A blood culture is relevant to the study's safety question because the outcome concerns whether L. reuteri was detected in blood after administration of the study product. The registry describes the trial as examining safety and tolerability, but the blood-culture endpoint is only one part of that broad topic. It does not measure every possible adverse effect, and a result about culture positivity cannot stand in for all safety outcomes.

The posted results report zero participants with a positive blood culture among the 40 assigned to Lactobacillus and zero among the 20 assigned to placebo. The registry does not report additional detail about culture collection, testing procedures, or how missing or inconclusive tests were handled. Without those details, interpretation should remain tied to the recorded endpoint and its stated follow-up timeframe.

7. Results Posted in the Registry

• Lactobacillus: 0.0% (0/40) versus 0.0% (0/20) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents the primary outcome as a participant count and also posts a risk-difference comparison. These measures answer related but distinct descriptive questions: the count records how many participants experienced the endpoint in each arm, while the risk difference expresses the absolute contrast between the arm-level outcome proportions. For a binary outcome, an event is counted as present or absent for each participant with an evaluable result. The registry does not report how it treated participants whose outcome status was unavailable.

What does a risk difference represent?

In general, a risk difference subtracts the outcome proportion in one group from the outcome proportion in the other. It is expressed on an absolute scale, rather than as a relative change. A value of 0.0 means the observed proportions do not differ on that scale. Here, both arms have zero recorded positive blood cultures, and the posted risk difference is 0.0. This describes the observed data; it does not establish that the underlying risks in the populations are equal.

The record identifies placebo as the control and lists the comparison for Lactobacillus. The direction of a risk difference depends on the order in which groups are contrasted. The posted estimate is 0.0, so the direction does not change its interpretation in this result. No inferential test statistic or p-value is reported. A reader should not infer a test result from the point estimate alone.

How should the interval limits be read?

In general, an interval around an estimate is intended to convey uncertainty from sampling, under a specified method and its assumptions. The posted comparison lists limits of 0.0 and 0.0 around the risk-difference estimate. The confidence level and interval method are not reported in the registry record. Because the limits coincide with the estimate, they do not communicate a useful range of sampling uncertainty. The registry does not provide another interval or an explanation for these values, so the limits should be reported as posted without treating them as evidence of perfect precision.

When no events are observed, the point estimate for an absolute difference can be zero, but the data still may be compatible with nonzero underlying event risks. General statistical methods account for uncertainty in event proportions; the specific method used for the posted limits is not reported. The value of an interval depends on its construction and assumptions, not only on its endpoints. The record does not provide enough methodological detail to assess those features.

What do randomization and masking contribute?

Random allocation is intended to make treatment assignment independent of measured and unmeasured baseline characteristics on average. It supports a comparison based on assigned groups, while chance imbalances can remain, especially in a trial of this size. Quadruple masking indicates that the record labels masking as quadruple, but the masked roles and procedures are not reported. Masking can reduce the influence of expectations on care and assessment, but the record does not describe how masking was maintained or evaluated.

The parallel model means the trial is recorded as comparing groups assigned to different arms rather than describing a crossover design. The posted arm counts are 40 for Lactobacillus and 20 for placebo. The analysis population and whether results follow assignment regardless of adherence are not reported. The reported arm counts therefore describe the outcome denominators in the registry results, but do not establish the handling of every randomized participant.

How should planning illustrations be distinguished from trial results?

General sample-size calculations use assumptions about the outcome, significance level, allocation, and effect to be detected. The planning description for this record specifies a two-sided significance level of 0.05, equal allocation, and a normal approximation, with target effects defined as fractions of the observed effect. These are assumptions for planning illustrations, not evidence that the original trial used those design choices. The record does not report the trial's own sample-size justification or statistical plan.

Planning illustrations are not observed power and do not change the interpretation of the trial results. In particular, a calculation based on an observed effect is conditional on that effect and on the stated assumptions. The record does not report the planning illustration values in the trial results, and no new sample-size calculation can be inferred from the posted counts alone. The registry also does not report interim analyses, adjustment methods, or a prespecified approach to multiplicity.

10. Confidence Intervals and Precision

The posted point estimate for the risk difference is 0.0, and its reported limits are 0.0 and 0.0. These limits do not show a range around the estimate, so they cannot be used to judge how precisely the population difference has been estimated. The registry record does not state the confidence level, the calculation method, or why the limits coincide with the estimate. No other uncertainty interval is reported.

In general, a confidence interval is a method-based range intended to show the sampling uncertainty associated with an estimate. It is not a guarantee that the true value lies within a particular range, and its interpretation depends on the statistical procedure and assumptions. Those details matter especially when the observed event count is zero in both groups. The observed absence of events yields a point comparison of zero, but it does not by itself demonstrate that the underlying event risks are zero or that they are equal.

The counts in the registry are 0.0 positive cultures among 40 participants in the Lactobacillus arm and 0.0 among 20 in the placebo arm. These denominators are relevant to precision, but the registry does not provide a usable interval for the individual arm risks or an adequately described interval for their difference. A p-value is also not reported. The posted data therefore permit a clear description of the observed counts and estimate, but not a complete assessment of inferential precision.

The average follow-up for the primary endpoint was 36 days. Precision and interpretation are tied to the endpoint, its ascertainment, and that recorded follow-up; the registry does not describe the timing or completeness of blood cultures for each participant. Any broader inference should account for that limited information rather than treating the reported zero limits as evidence of certainty.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures, but no secondary outcome results are posted. The primary outcome discussed in the record is the number of participants with a positive blood culture for L. reuteri. The registry record does not report whether other outcomes were prespecified, how outcome selection was handled, or whether statistical testing across outcomes was planned. It also does not report a multiplicity adjustment or a hierarchy of outcomes.

Multiplicity matters when several outcomes or comparisons are tested because the chance of obtaining an apparently unusual result can rise across a collection of tests. This is a general statistical concern, not evidence that a particular adjustment was or was not appropriate for this trial. With no secondary results and no reported testing plan, the scope of any multiplicity issue cannot be assessed. The primary comparison itself has no posted p-value.

The registry record does not report missing-data counts, reasons for missingness, imputation methods, or sensitivity analyses. It does not describe whether all randomized participants had evaluable blood cultures, how participants with incomplete follow-up were handled, or whether the posted denominators represent all randomized participants. The reported arm counts are 40 and 20, but these counts alone do not establish a missing-data strategy.

Analysis populations are also not reported in detail. The record does not say whether the primary analysis included participants according to randomized assignment, product receipt, adherence, or availability of an outcome measurement. Nor does it describe exclusions or protocol deviations. These details matter because different analysis populations can answer different questions and can affect how a randomized comparison is interpreted. The registry's posted result should therefore be read as a summary of the recorded outcome counts, with the analysis population and missing-data handling not reported in the registry record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event results report zero affected participants among 40 at risk in the Lactobacillus arm and zero among 20 at risk in the placebo arm. Deaths are reported as zero in each arm. These are distinct safety summaries from the primary blood-culture endpoint: the serious adverse-event counts cover a broader category, while the primary endpoint records positive blood cultures for L. reuteri.

The record also reports other adverse events in 28 of 40 participants in the Lactobacillus arm and 16 of 20 in the placebo arm. The registry does not provide the terms for these other events in the registry record, their severity, timing, duration, or whether investigators judged them related to study product. No serious adverse-event terms are listed in the record.

These counts describe what was recorded during the study; they do not establish that the product caused or did not cause an event. The registry record does not report detailed ascertainment procedures, missing safety data, or a comparative statistical analysis for these outcomes. In general, interpretation of adverse-event counts depends on definitions, follow-up, and completeness of reporting. The listed counts should therefore be read as descriptive safety results rather than as proof of an overall safety profile.

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

The central posted finding is that no positive blood cultures for L. reuteri were recorded in either trial arm. The estimated risk difference is 0.0, with limits reported as 0.0 and 0.0. This is a description of the observed primary endpoint in this trial. The registry record does not report a p-value, the confidence level or method for the limits, or an analysis that would support a broader claim about the underlying population risks.

The result does not show that the risk of a positive culture is exactly zero. A trial can observe no events while uncertainty about event occurrence remains, and the posted limits do not provide a useful account of that uncertainty. The result also does not show that all safety outcomes were absent: the registry reports other adverse events in both arms. Serious adverse events and deaths are reported as zero in each arm, but the record does not supply detailed event terms or attribution for the other adverse events.

The trial concerns healthy children aged 2-24 months, with Lactobacillus reuteri 17938 administered for five successive days and follow-up described as 3 months for safety outcomes. The primary endpoint timeframe is an average of 36 days. The findings should not be generalized automatically to other populations, products, durations, outcomes, or settings. The registry does not report enough detail about participant characteristics, outcome ascertainment, or analysis populations to evaluate those extensions.

Randomization and quadruple masking are features of the recorded design, but the registry does not describe the procedures in sufficient detail to assess their implementation. The result can be stated accurately as an absence of observed positive blood cultures in the posted groups. It should not be translated into a claim that the product works, does not work, or is definitively safe. Those conclusions would go beyond the endpoint and information reported.

14. Why This Trial Matters Statistically

This trial raises a basic statistical issue in safety research: an observed absence of a relatively specific event is not the same as certainty that the event cannot occur. The primary outcome records whether participants had a positive blood culture for L. reuteri. No positive cultures were reported in either arm, making the observed risk difference 0.0. The interpretation still depends on how much information the study contains about possible event risks and how completely outcomes were ascertained.

The posted interval limits illustrate why the method behind an estimate matters. Limits of 0.0 and 0.0 do not convey a useful range of uncertainty, and the registry does not identify the confidence level or calculation method. Readers should distinguish the point estimate from the uncertainty around it and should not treat a reported interval as informative without understanding its construction. This is a general lesson for binary outcomes with no observed events.

The design also makes clear why safety outcomes should be kept distinct. The primary blood-culture endpoint, serious adverse events, deaths, and other adverse events describe different aspects of the trial. The record reports zero serious adverse events and deaths in both arms, but other adverse events were recorded in each. A single endpoint cannot represent the full safety picture, and descriptive event counts do not establish causation.

Finally, the record illustrates the value of complete statistical reporting. Details about missing data, analysis populations, interval methods, and the prespecified analysis plan are not reported in the registry record. Without them, readers can describe the posted results but have limited ability to evaluate precision and analytic choices. That distinction is important when interpreting a Phase I trial designed around safety and tolerability.

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 primary endpoint is narrowly defined as a positive blood culture for L. reuteri. It does not capture all possible safety outcomes, and the registry does not report additional detail about culture collection, laboratory methods, or how inconclusive and missing tests were handled. The outcome timeframe is an average of 36 days, while the trial summary describes follow-up for 3 months; the record does not explain the relationship between these descriptions.

The posted primary result has zero events in both arms and a risk-difference estimate of 0.0. Its reported limits are also 0.0 and 0.0, but the confidence level and interval method are not reported. No p-value or alternative inferential analysis is reported. These gaps limit assessment of statistical precision. The registry also does not report the trial's statistical analysis plan, sample-size justification, interim analyses, or adjustment for multiple outcomes.

Although the design is listed as randomized, quadruple-masked, and parallel, the record does not explain random sequence generation, allocation concealment, masking procedures, or whether masking was maintained. Participant flow, withdrawals, adherence, protocol deviations, and analysis populations are not reported. Missing-data counts and methods are also absent, so the completeness of outcome ascertainment cannot be determined from the registry record.

The registry describes healthy children aged 2-24 months but does not report further participant characteristics or recruitment setting in the registry record. The results are consequently difficult to assess for applicability beyond the recorded population and study conditions. Other adverse events are reported as counts, but their terms and relationship to treatment are not described. These limitations make the posted findings useful as a record of observed outcomes, while restricting broader conclusions about safety and precision.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety of Lactobacillus Reuteri in Healthy Children Aged 2-24 Months — NCT02460575.
• Registry record last updated 2020-05-04; status last verified 2020-04.
• Results first posted 2020-05-04.
• 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

NCT02460575 is a completed, randomized, quadruple-masked, parallel-group Phase I trial sponsored by Tulane University School of Medicine. It enrolled healthy children aged 2-24 months, with 40 participants in the Lactobacillus arm and 20 in the placebo arm. The active product was given for five successive days, and the study summary describes follow-up for 3 months.

The primary endpoint was the number of participants with a positive blood culture for L. reuteri, with an average follow-up of 36 days. The posted count was zero in each arm, and the risk-difference estimate was 0.0, with reported limits of 0.0 and 0.0. The confidence level and method for those limits are not reported in the registry record.

Serious adverse events and deaths were reported as zero in each arm; other adverse events were reported in both arms. No secondary outcome results, p-value, detailed analysis population, or missing-data methods are reported. The findings describe the posted results for this trial and do not establish the broader safety profile of the product.