Study in Toddlers to Demonstrate Non-inferiority of GSK Biologicals' Hib-MenC & to Evaluate Persistence up to 5 Years.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study in Toddlers to Demonstrate Non-inferiority of GSK Biologicals' Hib-MenC & to Evaluate Persistence up to 5 Years. (NCT00326118), a randomized phase 3 study. The primary outcome is Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to 0.15 Micrograms Per Milliliter (µg/mL).

2. Clinical Question

The registry describes the primary phase as an evaluation of whether a single dose of Hib-MenC vaccine was non-inferior to commercially available Hib and MenC vaccines in toddlers who had been primed with Hib but not MenC. The primary endpoint was an antibody threshold rather than a clinical disease outcome. The registry says that a concentration at or above 0.15 µg/mL is indicative of short-term protection.

The posted primary counts are 292 of 292 in the Menitorix group and 100 of 100 in the Meningitec + Hiberix group. The posted risk difference is 0.0, with a confidence interval from 0.0 to 0.0. Those values describe the endpoint as recorded in the registry; they do not, by themselves, establish that a prespecified non-inferiority criterion was met. The non-inferiority margin and the formal testing procedure are not reported in the registry record.

The trial also had an extension phase in which blood samples were collected at Years 1, 2, 3, 4 & 5 to follow antibody persistence, with no additional vaccine administered in that phase. The registry lists antibody and safety outcomes beyond the primary endpoint, but numerical analyses for most are not reported in the registry record. The primary question should therefore be kept distinct from the longer-term persistence and broader safety questions.

3. Trial Design

This was a phase 3, randomized, parallel-group trial with no masking. The registry records an enrollment of 433 and a completed status. The study start is recorded as 2006-06-01 and primary completion as 2007-11-01. The sponsor was GlaxoSmithKline.

The comparison was between a Menitorix group and a Meningitec + Hiberix group. The arm descriptions state that participants in the Menitorix group received a single dose of Menitorix co-administered with Priorix. Participants in the comparator group received Meningitec co-administered with Hiberix and Priorix. The registry identifies the products as biological interventions. Details of the randomization sequence, allocation concealment, and the reason for the unequal posted group sizes are not reported in the registry record.

The primary endpoint was assessed one month after vaccination in the according-to-protocol cohort for immunogenicity. That cohort included participants for whom assay results were available for antibodies against at least one study vaccine antigen component from the blood sample taken at that time. The posted primary counts are 292 in the Menitorix group and 100 in the comparator group; these endpoint counts should not be confused with total enrollment. The adverse-event groups use denominators of 324 and 109, respectively.

The study had an extension phase intended to follow antibody persistence for up to 5 years after vaccination. The registry describes one blood sample at each of Years 1, 2, 3, 4 & 5 and states that no additional vaccine was administered during the extension phase. The extension design adds follow-up beyond the primary one-month assessment, but numerical persistence results are not reported in the registry record.

The registry does not report the planned sample-size justification, non-inferiority margin, interim analyses, detailed statistical analysis plan, or allocation concealment procedures. Those omissions limit how fully the design and its inferential claims 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.

Before assignment: Total of subjects completed in the previous period does not necessarily correspond to the amount of subjects who came back for the follow-up. These subjects were considered lost-to-follow-up.

Active Phase

Reasons for not completing this period:

Year 1 Follow-up

Year 2 Follow-up

Year 3 Follow-up

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the According-to-Protocol (ATP) cohort for analysis of immunogenicity which included subjects for whom assay results were available for antibodies against at least 1 study vaccine antigen component for the blood sample taken 1 month after vaccination.

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 With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to 0.15 Micrograms Per Milliliter (µg/mL), measured over 1 month after vaccination.

The primary endpoint was the number of subjects whose anti-polyribosylribitol phosphate (anti-PRP) antibody concentration was at least 0.15 µg/mL one month after vaccination. Anti-PRP is an antibody measure associated in the registry description with Hib vaccination. The endpoint reduces a measured antibody concentration to a threshold-based outcome: each participant is counted according to whether the result is at or above the stated cut-off.

The registry states that an anti-PRP concentration at or above 0.15 µg/mL is indicative of short-term protection. That makes the endpoint an immunogenicity marker with a stated biological interpretation, rather than a direct count of clinical infections or disease events. A participant crossing the threshold contributes to the count, but the endpoint does not describe how far above the threshold the concentration lies.

Threshold outcomes are useful for comparing the proportion of participants who meet a defined antibody criterion. However, converting a continuous concentration into a binary result discards information about the distribution and magnitude of antibody concentrations. The registry lists antibody concentrations as other outcomes, but numerical results for those measures are not reported in the registry record.

The endpoint was assessed in the according-to-protocol immunogenicity cohort. The record describes inclusion as requiring assay results for at least one study vaccine antigen component in the one-month blood sample. Therefore, its reported counts pertain to that analysis population, not necessarily every randomized participant. The exact non-inferiority margin and formal decision rule for this endpoint are not reported in the registry record.

7. Results Posted in the Registry

• Meningitec + Hiberix Group: 100.0% (100/100) versus 100.0% (292/292) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Subjects Reporting Unsolicited Symptoms

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Meningitec + Hiberix Group: 74.3% (81/109) versus 67.0% (217/324) on control; risk difference 7.3 percentage points (95% CI -2.3 to 17.0), risk ratio 1.11 (0.97–1.27); unadjusted two-proportion z-test p = 0.153.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Meningitec + Hiberix Group and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes covering meningococcal serogroup C antibody titers and threshold attainment, anti-PRP antibody concentrations and threshold attainment, and symptoms. It also describes antibody persistence follow-up through Years 1, 2, 3, 4 & 5. This range of outcomes extends the questions beyond the primary anti-PRP threshold at one month, including response measures for other vaccine components and longer-term antibody follow-up.

The numerical secondary comparison described in the posted results is unsolicited symptoms within 31 days after vaccination. The registry reports that 217 of 324 participants in the Menitorix group and 81 of 109 in the Meningitec + Hiberix group reported such symptoms. The risk difference is 0.073, with a confidence interval from -0.023 to 0.170, and the unadjusted p-value is 0.153. This is a safety-related secondary measure and does not provide further evidence about the primary anti-PRP endpoint.

The registry record does not report numerical results for most of the listed antibody outcomes or the extension-phase persistence assessments. It also lists 13 secondary outcomes as posted, while formal reported analyses are absent. The available results therefore do not support a comprehensive account of the pattern across all secondary endpoints, and absence of numerical results should not be interpreted as absence of an effect.

Unadjusted secondary results carry less weight when several outcomes are examined because the chance of at least one apparently notable result can increase across repeated tests. In general, prespecified multiplicity control or a clear hierarchy can help distinguish confirmatory results from exploratory ones. The registry does not report a multiplicity plan or identify a prespecified hierarchy. The secondary symptom comparison should consequently be interpreted as a single unadjusted result within a broader set of listed outcomes, rather than as a stand-alone confirmatory conclusion.

The primary and secondary outcomes also address different questions. The primary endpoint is a one-month antibody threshold, whereas unsolicited symptoms concern reported events over a short post-vaccination period. Neither should be used as a substitute for the other, and neither answers the extension-phase persistence question without the relevant follow-up results.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titers Above the Cut-off Values
• Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titers Above the Cut-off Values
• Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titers
• Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titers
• Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Above Cut-off Values
• Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Above Cut-off Values
• Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentrations
• Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentrations

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is binary: each participant either met the anti-PRP threshold or did not. A comparison of two groups can therefore be expressed as a difference in the proportions meeting the threshold. The posted primary proportions are 1.0 in each group, and the risk difference is 0.0. A risk difference of zero describes no observed separation in proportions for this endpoint; it is not, by itself, proof of equivalence or non-inferiority.

What does a confidence interval express?

In general, a confidence interval describes the range of effect values compatible with the data and the interval procedure, under that procedure’s assumptions. It reflects statistical uncertainty in the estimated comparison; it is not a guarantee that the true value lies within the interval. The primary interval is posted as 0.0 to 0.0. The registry record does not identify the interval method or explain this zero-width interval, so readers cannot assess from the record whether it reflects a particular calculation, reporting convention, or other feature of the analysis.

Non-inferiority testing has a specific structure. In general, it asks whether the data rule out a loss larger than a prespecified acceptable margin, using an interval or test defined in advance. The non-inferiority margin, statistical procedure, and decision rule for this trial are not reported in the registry record. Thus, the observed equality of the two proportions is descriptive evidence, but the formal non-inferiority conclusion cannot be reconstructed from the posted primary result alone.

Why does the analysis population matter?

The primary population is described as the according-to-protocol cohort for immunogenicity. It included participants with available assay results for antibodies against at least one study vaccine antigen component from the one-month blood sample. In general, an according-to-protocol analysis focuses on participants meeting specified protocol and measurement requirements. Its results may differ from analyses that retain all randomized participants, particularly if exclusions or missing measurements are related to response. The registry does not report an intention-to-treat primary analysis, the number excluded from the primary cohort, or detailed reasons for exclusion.

How should binary outcomes be read?

For a threshold endpoint, the group count and denominator show how many participants met the criterion among those analyzed. The primary counts are 292 of 292 and 100 of 100. Because each observed participant met the criterion, the observed proportions reach 1.0 in both groups. A binary threshold is easy to interpret, but it does not retain distinctions among antibody concentrations above the cut-off. The registry lists antibody concentration outcomes as well, but their numerical results are not reported in the registry record.

The secondary unsolicited-symptom comparison also uses a binary outcome. Its risk difference is 0.073, and its confidence interval ranges from -0.023 to 0.170. In general, an interval spanning zero is compatible with both a negative and a positive risk difference under the interval procedure. The unadjusted p-value is 0.153. These quantities describe the posted, unadjusted comparison; they do not establish that the groups are identical, and they are not adjusted for the number of outcomes considered.

What does over-dispersion mean in general?

Over-dispersion arises when observed variability exceeds what a statistical model expects. It is relevant for some count outcomes, where assuming an overly narrow variance can make uncertainty appear smaller than it is. The primary endpoint is a count of participants meeting a binary criterion, and the record gives no dispersion estimate or model specification. The registry does not report whether an over-dispersion assessment was relevant or performed. It would be inappropriate to infer a particular model from the endpoint label alone.

The posted planning illustration is based on the observed secondary risk difference, not on the trial’s own design. Its assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation. It gives participants per arm for 80% power and participants per arm for 90% power when planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. These values are planning illustrations, not observed power and not evidence that the original trial was designed using those assumptions. The sample-size justification for the trial is not reported in the registry record.

More generally, analyses of several outcomes raise the possibility of false-positive findings if each is tested without an adjustment or a prespecified hierarchy. The registry lists multiple secondary outcomes, but formal reported analyses are absent. The multiplicity strategy and any prespecified ordering of hypotheses are not reported in the registry record. Consequently, the unadjusted secondary comparison should be treated as exploratory rather than as a definitive confirmatory finding.

11. Confidence Intervals and Precision

The primary comparison has an observed risk difference of 0.0, with a posted confidence interval from 0.0 to 0.0. That interval communicates no uncertainty as written, but the registry record does not report the method used to calculate it or explain its zero width. It is therefore not possible to assess whether the interval reflects a suitable method for two groups in which every analyzed participant met the threshold. The posted values should be distinguished from an independently verified estimate of precision.

The endpoint counts are 292 of 292 in the Menitorix group and 100 of 100 in the Meningitec + Hiberix group. A complete observed response in both groups does not establish that the underlying probabilities are exactly 1.0. The primary interval, as posted, provides no visible allowance for uncertainty. Since the analysis method and non-inferiority margin are not reported in the registry record, the precision of the non-inferiority comparison cannot be fully evaluated.

For unsolicited symptoms, the risk difference is 0.073, with a confidence interval from -0.023 to 0.170. This interval includes zero and also includes differences in either direction. It therefore leaves room for a range of possible underlying group differences under the method used. The registry gives the interval but does not report the method used to calculate it.

Confidence intervals are generally more informative than a p-value alone because they show the range of effect estimates compatible with the data and method. However, their interpretation depends on the analysis population, model, and calculation procedure. Those details are not fully reported for these comparisons. Precision should therefore be discussed alongside the posted estimates without overstating what the intervals establish.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary antibody-threshold outcome and multiple secondary outcomes, including meningococcal antibody titers and cut-offs, anti-PRP antibody concentrations and cut-offs, and unsolicited symptoms. With multiple outcomes, statistical interpretation depends in part on whether hypotheses were ranked in advance, whether testing was adjusted for multiplicity, and which findings were intended to be confirmatory. A multiplicity plan, testing hierarchy, or adjustment procedure is not reported in the registry record.

The primary objective is described as non-inferiority, but the non-inferiority margin, formal test, and decision rule are not reported in the registry record. The primary confidence interval is posted as 0.0 to 0.0, and the record does not explain its calculation. Without those details, a formal non-inferiority claim cannot be assessed from the posted comparison alone. The observed equality in the analyzed sample is not a substitute for the prespecified margin and analysis plan.

The primary analysis population is the according-to-protocol immunogenicity cohort, defined by availability of assay results for at least one study vaccine antigen component in the one-month sample. The registry does not report a separate intention-to-treat result, the number of randomized participants omitted from the primary analysis, or the reasons for any omissions. Missing primary endpoint data and the handling of missing data are not reported in the registry record.

The extension phase was intended to collect one blood sample at Years 1, 2, 3, 4 & 5, with no additional vaccine during that phase. The registry record does not report follow-up denominators at those visits, loss to follow-up, missing-data methods, or numerical persistence analyses. This absence makes it difficult to assess the completeness and potential selection of the long-term follow-up results.

The record also does not report interim analyses, stopping rules, or a detailed statistical analysis plan. These omissions do not show that such procedures were absent; they mean that they cannot be evaluated from the registry record. The posted results can be described, but the prespecified inferential framework and its implementation are not fully available for assessment.

13. 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: asthma (0.9%), pneumonia (0.9%), pyrexia (0.9%), rash (0.9%), breath holding (0.3%).

The registry records serious adverse events among 4 of 324 participants in the Menitorix group and 2 of 109 participants in the Meningitec + Hiberix group. The listed serious-event terms and percentages are asthma, pneumonia, pyrexia, and rash at 0.9% each, and breath holding and convulsion at 0.3% each. The registry does not specify group-specific rates for those listed terms in the information.

These are descriptive safety counts. The denominators differ by group, and the recorded event counts are small. The registry does not report a comparative statistical analysis of serious adverse events, so the figures should not be treated as evidence of a precise between-group difference or similarity. A serious adverse event is also distinct from an unsolicited symptom: the latter is reported separately for the period within 31 days after vaccination.

Deaths are not reported in the registry record. That does not establish that none occurred; it indicates that a death count is not available in the record. The safety figures do not establish a complete safety profile, and they should not be interpreted as medical advice or as a treatment recommendation.

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

The primary result describes a high observed threshold-attainment count in each analysis group: 292 of 292 in the Menitorix group and 100 of 100 in the Meningitec + Hiberix group. Both posted proportions are 1.0, and the reported risk difference is 0.0. This is the observed pattern for the one-month anti-PRP threshold in the according-to-protocol immunogenicity cohort.

The result does not establish that the underlying response probabilities are exactly equal. Nor does equality of the observed proportions alone establish non-inferiority. A formal non-inferiority interpretation requires the margin and analysis procedure, neither of which is reported in the registry record. The confidence interval is posted as 0.0 to 0.0, but the record does not explain how it was obtained, limiting interpretation of precision.

The endpoint is an antibody marker with a registry-stated interpretation as indicative of short-term protection. It is not a direct count of disease events. It does not establish a difference in clinical illness, the duration of protection, or the persistence of antibody through the extension follow-up. The planned blood sampling at Years 1, 2, 3, 4 & 5 is described, but numerical results for those visits are not reported in the registry record.

The trial’s secondary symptom comparison is separate from the immunogenicity endpoint and is unadjusted. Its estimate and interval describe a range of possible differences under the reported analysis, but do not resolve the primary non-inferiority question. The registry does not report numerical analyses for most listed secondary outcomes or a multiplicity plan.

These limits are important when interpreting a registry result: the counts and estimates describe what is posted, while missing design and analysis details restrict conclusions about the prespecified statistical claim. The result should be read as an immunogenicity comparison in a defined analysis cohort, not as a comprehensive account of clinical effectiveness, long-term persistence, or comparative safety.

15. Why This Trial Matters Statistically

This trial illustrates why the observed point estimate and the inferential question are not the same. The two primary group proportions are both 1.0 and the risk difference is 0.0, but the trial’s stated objective is non-inferiority. That objective requires a prespecified margin and a formal analysis; neither is reported in the registry record. Identical observed proportions are therefore not enough, on their own, to verify the intended claim.

It also demonstrates the importance of examining the endpoint and analysis population together. The outcome is a threshold-based antibody measure rather than a clinical event, and the primary counts pertain to the according-to-protocol immunogenicity cohort. Those features define what the result can speak to. The threshold gives a clear classification, while omitting information about how far antibody concentrations lie above or below it.

The record also raises a precision question: its primary interval has zero width, despite being a comparison of two groups with finite counts. Since the interval method is not described, readers cannot determine how the posted interval should be evaluated. Transparent methods matter particularly when a confidence interval is central to a non-inferiority conclusion.

Finally, the registry lists multiple secondary and extension outcomes, but numerical results for most are not reported. This makes it important to distinguish the primary result from a broader evidence base that cannot be reconstructed from the registry record. The trial is a useful example of how endpoint definition, analysis population, interval construction, multiplicity, and complete outcome reporting jointly shape statistical interpretation.

16. 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 does not report the non-inferiority margin, formal testing procedure, or decision rule. Although the primary proportions are both 1.0, the posted comparison alone cannot verify that the prespecified non-inferiority criterion was met. The primary confidence interval is 0.0 to 0.0, and the record does not explain the interval method or the zero width.

The primary result is based on an according-to-protocol immunogenicity cohort with available assay results for at least one study antigen component at one month. The record does not provide a corresponding intention-to-treat analysis, detailed cohort flow, reasons for exclusions, or missing-data methods. This restricts assessment of how the analysis population relates to all randomized participants.

The registry gives an enrollment of 433, while the posted primary endpoint counts are 292 and 100 and the safety denominators are 324 and 109. These figures refer to different reported analysis contexts, but the record does not provide a full participant flow explaining the denominators. The randomization method, concealment procedures, and reason for the unequal group sizes are also not reported.

Numerical results for most listed secondary outcomes and for antibody persistence through Years 1, 2, 3, 4 & 5 are not reported in the registry record. The record does not report a multiplicity plan, interim analyses, or a detailed statistical analysis plan. Serious adverse event counts are descriptive, and deaths are not reported in the registry record. These limitations make it difficult to assess completeness, precision, and the full scope of the trial’s statistical conclusions.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Study in Toddlers to Demonstrate Non-inferiority of GSK Biologicals' Hib-MenC & to Evaluate Persistence up to 5 Years. — NCT00326118.
• Registry record last updated 2018-08-24; status last verified 2016-09.
• Results first posted 2009-10-23.
• 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.

20. Record Summary

NCT00326118 was a completed, randomized, parallel-group phase 3 trial with no masking and an enrollment of 433. It compared Menitorix co-administered with Priorix against Meningitec co-administered with Hiberix and Priorix in toddlers primed with Hib but not MenC. The primary endpoint was the number reaching an anti-PRP antibody concentration of at least 0.15 µg/mL one month after vaccination, assessed in the according-to-protocol immunogenicity cohort.

The primary counts were 292 of 292 and 100 of 100, with a posted risk difference of 0.0 and confidence interval from 0.0 to 0.0. The registry describes the objective as non-inferiority, but the margin and formal decision procedure are not reported in the registry record. The study also planned antibody persistence follow-up through Years 1, 2, 3, 4 & 5; numerical persistence results are not reported in the registry record.