Assess Reacto- and Immunogenicity of Pneumococcal Conjugate Vaccine When Given as Booster or a 2 Dose Catch up Schedule: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assess Reacto- and Immunogenicity of Pneumococcal Conjugate Vaccine When Given as Booster or a 2 Dose Catch up Schedule (NCT00513409), a non-randomized phase 2 study. The primary outcome is Number of Subjects Reporting Grade 3 Symptoms (Solicited and Unsolicited).

2. Clinical Question

The central statistical question concerns the frequency of severe symptom reports in the two vaccination schedules, not a randomized comparison of otherwise interchangeable groups. The booster group had previously received Synflorix, whereas the catch-up group had previously received Havrix co-administered with Infanrix hexa. Their current study schedules also differed in the co-administered vaccines. These differences are important when interpreting any contrast: observed differences could reflect prior vaccination history, the current schedule, or other differences between the groups, rather than the effect of a single vaccine component alone.

The primary outcome is a count of participants meeting a symptom criterion during a defined period after vaccination. The record also identifies reactogenicity, safety, and immunogenicity as study interests and lists measures of local and general symptoms, adverse events, and antibody or functional activity thresholds. However, numerical results for the primary symptom endpoint and the listed immunogenicity outcomes are not reported in the registry record. The available description therefore defines the question the study was designed to address, but does not establish the observed frequency of Grade 3 symptoms or provide an estimate of a between-group effect.

3. Trial Design

This was a Phase II, observer-blind follow-up study with a parallel-group structure and non-randomized allocation. The registry lists enrollment of 163 participants and identifies the study as completed. The study start date was 2007-08-22, and the primary completion date was 2008-02-20. GlaxoSmithKline is listed as the sponsor. The registry describes the participants as healthy children younger than 3 years.

The two groups followed distinct vaccination histories and schedules. Children in the Synflorix Booster Group had previously been primed with Synflorix. In the current study they received Havrix co-administered with Infanrix hexa as Dose 1 and Synflorix as Dose 2. Children in the Synflorix Catch-up Group had previously been primed with Havrix co-administered with Infanrix hexa. In the current study they received Synflorix co-administered with Infanrix hexa as Dose 1 and Synflorix as Dose 2. Thus, the comparison is between two schedule groups, not between a vaccine group and an untreated control group.

Observer-blind describes the masking recorded for the study, but the registry record does not specify which individuals were masked or how masking was maintained. Non-randomized allocation means the record does not describe random assignment to the schedules. Accordingly, comparisons between groups are descriptive and may be influenced by pre-existing differences, including the different priming histories. The registry itself cautions that the arms are not a like-for-like control comparison.

The posting concerns objectives and outcome measures of the booster phase. It states that objectives and measures for the primary phase are presented in a separate protocol posting, NCT00338351. The registry record does not report the rationale for the enrollment target, the method used to determine it, or other protocol details beyond the design and schedule descriptions. It lists 11 outcome measures, while the number of analyses recorded is 0. Those entries limit the available basis for reconstructing the prespecified analysis plan or evaluating the completeness of reported results.

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: Analysis was performed on all subjects included in the Total Vaccinated Cohort, who returned the symptom sheet.

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 Subjects Reporting Grade 3 Symptoms (Solicited and Unsolicited), measured over Within 4 days after the administration of any study vaccine dose.

The primary endpoint is the number of participants reporting Grade 3 solicited or unsolicited symptoms within 4 days after administration of any study vaccine dose. It is a participant count, rather than a count of every symptom episode. The Grade 3 definition focuses on functional impact: symptoms prevent normal, everyday activities. The registry gives examples involving a young child’s attendance at school, kindergarten, or a day-care center, and the possibility that a parent or guardian would seek medical advice.

This kind of endpoint is used to describe the severity of short-term symptoms following vaccination. Combining solicited and unsolicited symptoms allows the measure to include symptoms specifically sought through the study process as well as symptoms reported without being specifically solicited. The defined observation window also makes clear that the endpoint concerns symptoms in the period after a study dose, rather than symptoms at any time during follow-up.

The analysis population is described as all participants included in the Total Vaccinated Cohort who returned the symptom sheet. That qualification matters: the endpoint result would reflect symptom reports among participants meeting that population definition, not necessarily every enrolled child. The registry record does not report the number meeting the endpoint, the corresponding proportion, or an estimate comparing the groups. It therefore gives the outcome definition and analysis population, but not the result needed to describe how often Grade 3 symptoms occurred.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several design and analysis concepts help explain what can and cannot be inferred from the registry record. The essential distinction is between describing outcomes in the two observed groups and estimating a causal effect of one schedule compared with another. The record supports the former only to the extent that it posts counts; it does not document a randomized comparison or a full statistical analysis.

What does non-randomized allocation imply?

In a randomized trial, chance assignment is used to make treatment groups comparable, on average, with respect to measured and unmeasured characteristics. This study is listed as non-randomized. General statistical interpretation therefore treats a between-group contrast as potentially confounded: group membership may be associated with characteristics that also relate to symptom reporting or adverse events. Here, the registry explicitly describes different prior priming histories and different vaccine co-administration schedules. Those differences are directly relevant to interpreting a contrast, and the record cautions that the arms are not a like-for-like control comparison.

This does not make descriptive reporting uninformative. Counts can describe what was recorded among participants in each group. But descriptive counts alone cannot isolate which component of a complex schedule is associated with an outcome. The registry record does not report an adjusted analysis, the covariates that might have been considered, or a method for addressing differences between groups.

How should a participant count be understood?

The primary endpoint is the number of participants who reported Grade 3 solicited or unsolicited symptoms within 4 days of any study vaccine dose. It counts participants meeting the definition, not the total number of symptoms. The threshold is based on symptoms preventing normal, everyday activities, with examples tied to a young child’s attendance and the caregiver seeking medical advice. The endpoint is therefore a thresholded, binary outcome at the participant level: each participant either meets the criterion for the endpoint or does not, as recorded under the study definition.

For a binary outcome, a count is often interpreted alongside the number of participants assessed. A proportion can describe how common the outcome was in the analyzed group, while a comparison may quantify the difference between groups. The registry record does not provide the primary endpoint counts or the relevant denominators for that endpoint, so neither a proportion nor a group contrast can be stated. No new estimate should be inferred from enrollment or from the serious adverse event counts, because those are different measures and populations may differ.

What does the analysis population mean?

The primary analysis population is described as all subjects included in the Total Vaccinated Cohort who returned the symptom sheet. This connects the endpoint to both vaccination and availability of a returned symptom sheet. It is not simply described as everyone enrolled. If participants do not return a symptom sheet, their symptoms may not be captured by this endpoint analysis. General missing-data principles emphasize that missing reports can affect both the number analyzed and the interpretation of symptom frequency, especially if return is related to symptoms or other participant characteristics. The registry does not say how missing sheets, incomplete symptom forms, or other missing observations were handled.

What does observer-blind tell the reader?

The registry describes the study as observer-blind and lists double masking. Masking can, in general, reduce the influence of expectations on outcome assessment or reporting. Its relevance depends on who was masked, how masking was maintained, and whether the outcome is susceptible to observer or participant expectations. The record does not specify those operational details, so the masking label should not be expanded into assumptions about particular people or procedures.

How should confidence intervals and significance tests be read?

In general, a confidence interval communicates the precision of an estimate under a specified statistical model. A narrow interval indicates greater precision than a wide interval, while an interval alone does not eliminate bias from a non-randomized design. A significance test addresses compatibility with a specified null hypothesis under its assumptions; it does not measure clinical importance or correct confounding. The registry record lists 0 analyses and gives no primary endpoint estimate, confidence interval, or test result. There is consequently no reported inferential result to interpret for the primary endpoint.

What are the sample-size illustrations for?

The registry’s planning assumptions describe illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. These are planning illustrations, not observed power and not the trial’s own design justification. In general, such illustrations show how a hypothetical study size would depend on the effect one aims to detect and the statistical assumptions used. The registry record does not report the study’s sample-size justification, and no observed primary endpoint effect is reported in this record. The illustrative assumptions therefore cannot be treated as evidence that the study was adequately powered for its primary endpoint.

Over-dispersion is a general concern when data vary more than a simple statistical model expects. It can make standard errors too small and confidence intervals too narrow if the model fails to account for extra variability. The primary outcome is described as a participant count for a binary symptom criterion, but no model for the primary analysis is reported. The record does not establish that over-dispersion was assessed or that a particular model was used; discussion of the concept should not be mistaken for a description of this study’s analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including the primary measure of Grade 3 symptoms and secondary measures covering solicited local and general symptoms, unsolicited adverse events, serious adverse events, and immunogenicity. Considering multiple outcomes can increase the chance of at least one apparently notable result when many statistical tests are performed. General approaches to multiplicity include prespecifying a primary outcome, adjusting inference across selected tests, or clearly treating secondary findings as exploratory. The registry record does not report whether a multiplicity procedure was planned or used, nor does it give a hierarchy or testing strategy for the outcome measures.

The record lists 0 analyses. It therefore does not document which outcomes were analyzed, which statistical methods were used, or whether any adjustment for multiple comparisons was made. The absence of these details prevents evaluation of the statistical interpretation of any unposted analyses; it is not evidence that a specific method was or was not used outside the registry record.

For the primary endpoint, the stated population includes Total Vaccinated Cohort participants who returned the symptom sheet. This implies that participants without a returned sheet are not included in the endpoint population as described. The number of participants with missing sheets, the treatment of incomplete forms, and any imputation or sensitivity analyses are not reported in the registry record. In general, missing outcome information can limit precision and can bias an estimate if the likelihood of missingness is related to the outcome or participant characteristics. The available description does not permit assessment of whether missingness was balanced across the groups or related to symptoms.

The record also does not report a detailed participant flow for the primary endpoint, the number assessed for each outcome, or reasons for any exclusions. The stated analysis population should therefore be kept distinct from total enrollment of 163. Without endpoint-specific denominators and missing-data details, the completeness of the symptom reporting cannot be judged from the registry record.

11. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: thermal burn (1.2%).

The registry reports serious adverse events among participants at risk in each group. In the Synflorix Booster Group, 1 of 84 participants at risk was recorded with a serious adverse event. In the Synflorix Catch-up Group, 0 of 79 participants at risk was recorded with a serious adverse event. These are observed counts, not adjusted comparisons, and they do not establish that one schedule has a higher or lower underlying risk.

With uncommon outcomes, a small change in the number of recorded events can have a substantial effect on how the group counts appear, while the underlying risk remains uncertain. General interpretation of safety counts therefore considers the number of participants assessed, the event definitions, follow-up duration, and uncertainty around estimates. The registry record does not provide confidence intervals or a statistical comparison for these serious adverse event counts.

The record lists Thermal burn at 1.2% among the top serious terms. It does not provide further detail about the event in this summary, such as its timing, relationship assessment, or group attribution. The serious adverse event counts should also not be confused with the primary endpoint, which concerns Grade 3 symptoms within 4 days after any study dose. These are distinct outcomes with distinct definitions and reporting windows.

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

The record describes a study of reactogenicity, safety, and immunogenicity in healthy children younger than 3 years receiving Synflorix as a booster or as part of a two-dose catch-up schedule. Its primary endpoint is the number of participants reporting Grade 3 solicited or unsolicited symptoms within 4 days after any study dose. The endpoint definition clarifies what counted as Grade 3, but the registry record does not report the observed primary endpoint result.

The posted serious adverse event counts are 1 of 84 in the booster group and 0 of 79 in the catch-up group. These counts describe the recorded events among the participants at risk. They do not prove that the schedules differ, and they do not establish a causal relationship between a schedule and an adverse event. The non-randomized design and distinct prior vaccination histories further limit causal interpretation of any comparison between groups.

The registry lists secondary outcomes that include symptoms, adverse events, and measures of vaccine-specific antibody concentrations and opsonophagocytic activity. Listing an outcome does not report its result. Numerical results for those immunogenicity outcomes, as well as the primary endpoint result, are not reported in the registry record. Accordingly, the record cannot support a statistical conclusion about the measured immune responses or the frequency of Grade 3 symptoms.

In general, a study’s result should be read together with its estimate, uncertainty, analysis population, and design. Here, the record provides limited safety counts and defines several outcomes but documents 0 analyses. It does not report primary endpoint estimates, confidence intervals, or between-group tests. The appropriate interpretation is therefore bounded: the registry identifies what was measured and gives certain event counts, while leaving the magnitude and precision of the main symptom outcome unreported. It does not establish that either schedule is effective or ineffective, or that one is safer than the other.

13. Why This Trial Matters Statistically

This study is statistically notable because it illustrates the difference between a two-group study and a randomized comparison. The parallel-group format may invite readers to compare outcomes between the booster and catch-up groups, but allocation was non-randomized and the groups had different priming histories. The registry cautions that the arms are not a like-for-like control comparison. This makes design context essential: a group contrast is not automatically an estimate of the causal effect of a schedule.

The record also highlights the importance of separating an endpoint definition from an endpoint result. The Grade 3 symptom measure is described with a defined severity threshold, a specified time window, and an analysis population tied to returned symptom sheets. Those details are valuable for understanding what the study intended to count. But without the observed count, denominator, or estimate, readers cannot determine the frequency or precision of the primary outcome.

A further statistical lesson is that outcome lists do not substitute for documented analyses. The registry identifies multiple safety and immunogenicity measures, but lists 0 analyses. Without reported methods and results, it is not possible to assess the handling of multiple outcomes, missing reports, or uncertainty in estimates. The serious adverse event counts offer a limited descriptive account, not a full analysis of safety differences.

Finally, the planning assumptions described for sample-size illustrations should not be mistaken for the trial’s own design rationale or for evidence of adequate power. They are planning illustrations based on an observed effect, while the registry does not report the primary endpoint effect or the study’s sample-size justification. Taken together, these features show why statistical interpretation depends not only on the outcome labels, but also on allocation, analysis populations, event counts, and transparent reporting of estimates and uncertainty.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most direct limitation for interpretation is that the primary endpoint result is not reported in the registry record. Although the symptom definition, time window, and analysis population are described, the number of participants meeting the endpoint is absent. The record therefore does not allow a numerical description of the primary outcome or its precision.

Non-randomized allocation is a trial-specific limitation for comparisons between the two schedule groups. Participants had different priming histories, and the current study vaccine combinations also differed. As the registry notes, the arms are not a like-for-like control comparison. Any apparent difference between groups could reflect these schedule and history differences or other differences between participants.

The primary analysis population was limited to Total Vaccinated Cohort participants who returned the symptom sheet. The record does not report how many symptom sheets were missing or incomplete, how missing observations were handled, or whether sensitivity analyses were performed. Endpoint-specific denominators are also not reported. These omissions limit assessment of outcome completeness and the possibility of bias from missing reports.

Although the study is described as double masked and observer-blind, the registry does not specify who was masked or the procedures used. The record also lists 11 outcome measures and 0 analyses, without reporting a statistical analysis plan, multiplicity handling, confidence intervals, or primary endpoint comparisons. The study’s sample-size justification is not reported in the registry record. Finally, the serious adverse event counts are limited descriptive information and do not include reported comparative uncertainty. These limitations concern interpretation of this registry record; they do not establish what may have been reported elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Assess Reacto- and Immunogenicity of Pneumococcal Conjugate Vaccine When Given as Booster or a 2 Dose Catch up Schedule — NCT00513409.
• Registry record last updated 2018-12-19; status last verified 2018-05.
• Results first posted 2009-08-11.
• 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.

18. Record Summary

NCT00513409 is a completed Phase II, observer-blind follow-up study sponsored by GlaxoSmithKline. The registry lists non-randomized allocation, a parallel-group model, and enrollment of 163 healthy children younger than 3 years. The study compared a Synflorix booster schedule in previously primed children with a two-dose catch-up schedule in children with a different priming history. The study start date was 2007-08-22, and the primary completion date was 2008-02-20.

The primary outcome was the number of participants reporting Grade 3 solicited or unsolicited symptoms within 4 days after any study vaccine dose. The stated analysis population comprised Total Vaccinated Cohort participants who returned the symptom sheet. The registry lists 11 outcome measures and 0 analyses, and does not report the primary endpoint result. Serious adverse events were recorded in 1 of 84 participants at risk in the booster group and 0 of 79 in the catch-up group. Because allocation was non-randomized and the groups had different vaccination histories, these counts should be interpreted descriptively rather than as a like-for-like comparison.