Year 3 Extension for Efficacy Follow-up in Subjects Vaccinated in Studies Rota-028, 029 or 030 (NCT00197210): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Year 3 Extension for Efficacy Follow-up in Subjects Vaccinated in Studies Rota-028, 029 or 030 (NCT00197210) (NCT00329745), a randomized phase 3 study. The primary outcome is Number of Subjects With Severe Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strains.

2. Clinical Question

The registry frames the question as a comparison of the number of participants with a qualifying severe rotavirus gastroenteritis episode during the follow-up period. The endpoint is restricted to episodes in which rotavirus other than the vaccine strain was identified in a gastroenteritis stool sample. The record says this outcome was secondary in the study protocol. It is presented as the primary outcome in this registry summary because none of the protocol’s primary outcome measures applied to the Year 3 follow-up time point summarized.

This distinction matters when interpreting the result. The displayed analysis concerns a particular follow-up period and endpoint, not every outcome assessed in the parent studies or across the full study program. The registry record does not report the parent protocol’s other primary endpoint results in this Year 3 summary. The extension’s focus is the persistence of observed differences in severe wild-type rotavirus gastroenteritis during the stated period among participants in the efficacy cohort.

3. Trial Design

This was a Phase III, randomized, triple-masked, parallel-group, placebo-controlled, multi-country and multi-center study. The registry lists enrollment of 8687. Its title identifies the study as a Year 3 extension for efficacy follow-up of subjects vaccinated in Rota-028, Rota-029 or Rota-030. The listed start is 2007-01, primary completion is 2008-07, and status is completed.

The extension followed participants who had received two oral doses of either Rotarix or placebo during a parent study. The dosing schedules in those studies differed: the Rota-028 schedule was at 3 and 4 months of age, while Rota-029 and Rota-030 used 2 and 4 months of age. The record identifies Rotarix as a biological intervention and placebo as the comparator. It does not describe additional study treatment during the extension.

For the efficacy endpoint summarized, the analysis population is the according-to-protocol cohort for efficacy. The endpoint counts participants with severe rotavirus gastroenteritis caused by circulating wild-type strains from Year 2 up to Year 3. The analysis counts were 4222 in the Rotarix group and 4185 in the placebo group. These are the group counts reported for this efficacy comparison; they should not be substituted for the overall enrollment figure or the different safety risk sets.

Triple masking indicates that the registry classifies the study as triple-masked, but it does not identify which roles were masked or how masking was maintained. The precise randomization procedure, allocation ratio in the trial, site details, and operational features of the extension are not reported in the registry record. The equal allocation assumption mentioned for planning illustrations is an assumption for those illustrations, not a reported description of the trial’s actual allocation.

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 the According-to-Protocol (ATP) cohort for efficacy.

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 Severe Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strains, measured over From Year 2 up to Year 3.

The endpoint is the number of participants with severe rotavirus gastroenteritis caused by circulating wild-type rotavirus strains during the period from Year 2 up to Year 3. A qualifying episode had to be severe gastroenteritis in which rotavirus other than the vaccine strain was identified in a gastroenteritis stool sample. The measure is therefore a participant count for a specified event and follow-up period, rather than a count of all gastroenteritis episodes or all rotavirus infections.

This endpoint is used to describe severe disease attributable to circulating wild-type strains during the extension. Restricting the definition to severe episodes and requiring identification of rotavirus in a stool sample makes the outcome more specific to the stated clinical event than an endpoint based only on nonspecific gastrointestinal symptoms. The registry does not give further detail about the severity criteria, laboratory procedures, or event adjudication process, so those aspects are not reported in the registry record.

The record notes that this measure was secondary in the study protocol. It is reported as primary in the Year 3 registry summary because none of the protocol’s primary outcome measures pertained to the Year 3 follow-up time point presented. The label in this summary should therefore be read in light of that explanation rather than as evidence that the endpoint was the protocol’s original primary measure.

7. Results Posted in the Registry

• Rotarix Group: 0.0% (0/4222) versus 0.3% (13/4185) on control; risk difference -0.3 percentage points (95% CI -0.5 to -0.1); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The reported measure is a binary participant outcome: each participant either had at least one qualifying event during the stated follow-up or did not. In general, a risk is the proportion of participants in a group who experience the event. A risk difference subtracts one group’s risk from the other group’s risk. It is an absolute measure, so it describes the difference on the risk scale rather than the relative size of one group’s risk compared with the other.

For this comparison, the direction is Rotarix minus placebo. The estimate is -0.003. A negative value indicates a lower estimated risk in the Rotarix group than in the placebo group. This is the registry’s reported comparison; the group counts and estimate should be read together, because the count difference alone does not express the uncertainty or the size of the absolute risk contrast.

What does the confidence interval add?

In general, a confidence interval gives a range of values compatible with the data and the interval-producing method, under its assumptions. It communicates precision as well as direction. The reported interval runs from -0.005 to -0.001. Both limits are negative, so the interval as posted does not include a risk difference of zero. The registry does not report the confidence level or the calculation method, so those details are not inferred.

In general, narrower intervals indicate greater precision than wider intervals when the same measure and method are used. Interval width is affected by the amount of information in the data, including the number of events, as well as the analysis method. Here, event counts are sparse, and the interval is an important complement to the point estimate. It does not capture every limitation, such as possible selection into the efficacy cohort or uncertainty from outcome ascertainment.

How should the p-value be read?

The reported p-value is p < 0.001. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test’s assumptions were true. It is not the probability that the null hypothesis is true, nor is it a measure of effect size. The p-value does not show whether the estimated difference is important for patients or whether the result is free of bias.

The registry record does not identify the test used to obtain the p-value, whether it was adjusted, or the complete statistical model. It also does not report a separate inferential procedure for the risk difference. As a result, the posted estimate, interval, and p-value can be described, but the exact computational details cannot be reconstructed from the registry record.

Why do the event counts matter?

In general, sparse binary outcomes can make estimates less stable because each observed event carries substantial information about the group risk. When one group has no observed events, methods for intervals and tests may differ in how they handle that boundary case. The registry record does not report which method was used. The observed zero is a count in this analysis, not proof that the underlying event risk is exactly zero.

Over-dispersion is a general concern when data vary more than a chosen statistical model expects. It is often discussed for count outcomes with repeated events or clustered data. This endpoint is reported as the number of participants with an event, rather than a count of every episode per participant, and the record does not report a model for over-dispersion. It would therefore be inappropriate to claim that over-dispersion was assessed or to infer a model choice from the posted counts.

What does the planning information mean?

In general, sample-size planning illustrations ask how many participants might be needed under specified assumptions to detect an effect at a chosen significance level and power. The registry’s stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation; the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not a description of the trial’s observed allocation or its original design justification.

Any such participant counts are planning illustrations, never observed power. Observed power is not a useful substitute for describing the observed estimate and its uncertainty. The record does not report the trial’s own sample-size justification, its assumed effect for planning, or whether the posted illustration assumptions were used in the trial design.

Important analysis details are not reported in the registry record, including the confidence interval method, statistical test, covariate adjustment, stratification, interim analyses, and prespecified handling of multiplicity. The registry reports the analysis population and endpoint definition, but it does not provide enough detail to reproduce the inferential analysis independently.

10. Confidence Intervals and Precision

The risk-difference estimate is -0.003, with a confidence interval from -0.005 to -0.001. The entire reported interval is on the negative side of zero, indicating that the interval is consistent with a lower estimated event risk in the Rotarix group than in the placebo group. The posted p-value is p < 0.001. These results describe statistical evidence and uncertainty for the reported comparison; they do not, by themselves, establish clinical importance or eliminate the possibility of limitations in the analysis.

In general, a confidence interval shows the range of values compatible with the data under the method’s assumptions. Its width is a measure of precision: a wider interval would indicate less precise estimation than a narrower one, all else being equal. The reported limits provide more information than the point estimate alone because they show uncertainty around the estimated difference. The registry does not state the confidence level or interval calculation method, so these should not be assumed.

The sparse event counts are relevant to precision. There were 0 endpoint events among 4222 participants in the Rotarix efficacy group and 13 among 4185 in the placebo efficacy group. The absence of observed events in one group does not establish that its underlying risk is exactly zero. With few events, the estimate can be sensitive to the individual outcomes observed, and the interval is essential context for interpreting the point estimate.

The reported interval quantifies statistical uncertainty under its calculation method; it does not cover every source of uncertainty. It does not describe the consequences of missing outcome information, selection into the according-to-protocol cohort, possible differences in follow-up, or limitations in event classification. Those details are not reported in the registry record. Precision should therefore be understood as precision of the posted comparison, not as a complete measure of certainty about every interpretation of the study.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the severe wild-type rotavirus gastroenteritis outcome as secondary in the study protocol, while presenting it as the primary outcome measure in this Year 3 summary because none of the protocol’s primary measures covered the follow-up time point reported. This distinction is relevant to multiplicity: the posted finding is one outcome in a larger study context, and the record does not describe how the number of outcomes or analyses was accounted for statistically.

Whether a multiplicity adjustment was planned or applied is not reported in the registry record. The record also does not report interim analyses, a hierarchy of endpoints, or a prespecified statistical analysis plan for this extension. The posted p-value should therefore be read as the value associated with the registry comparison, not as evidence that multiplicity was addressed by a particular method.

The efficacy population is identified as the according-to-protocol cohort for efficacy. The registry does not report how many participants were excluded from that cohort, why any were excluded, how many lacked endpoint information, or how missing data were handled. It does not state whether participants with incomplete follow-up were excluded, counted as not having an event, or addressed using another approach. No such procedure should be inferred.

These reporting gaps matter because analysis populations and missing-data procedures can affect the interpretation of a group comparison. The available efficacy group counts describe the analyzed cohort but do not explain how it relates participant by participant to total enrollment. Safety risk sets are reported separately and should not be treated as the efficacy denominators. The registry record does not provide enough information to assess the impact of exclusions or missingness on the estimated difference.

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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: upper respiratory tract (0.1%), gastroenteritis (0.1%), idiopathic thrombocytopenic purpura (0.0%), intussusception (0.0%), gastritis (0.0%).

The registry reports serious adverse events for separate safety risk sets: 10 among 4359 participants in the Rotarix group and 11 among 4328 in the placebo group. These are group counts for participants at risk in the safety reporting, not the efficacy cohort counts used for the rotavirus gastroenteritis comparison. They should be interpreted as descriptive safety information in the registry record.

The record also lists percentages for serious adverse event terms, including Upper respiratory tract at 0.1%, Gastroenteritis at 0.1%, Idiopathic thrombocytopenic purpura at 0.0%, Intussusception at 0.0%, Gastritis at 0.0%, and Lymphadenitis at 0.0%. These displayed percentages are rounded as reported. A displayed value of 0.0% should not be treated as a precise estimate of zero risk, and the record does not provide term-specific event counts alongside these percentages.

The registry lists zero under its other adverse event measure for both groups. Deaths are not reported in the registry record. The available summary does not describe event seriousness criteria, relatedness assessments, timing, or detailed methods for collecting adverse events. These figures alone do not establish causation, nor do they support a complete comparison of safety across all potential events.

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

The posted efficacy comparison shows 0 participants with severe wild-type rotavirus gastroenteritis in the Rotarix group and 13 in the placebo group during the stated Year 2 to Year 3 period. The risk-difference estimate is -0.003, with a confidence interval from -0.005 to -0.001 and p < 0.001. These are the observed counts and statistical comparison in the according-to-protocol efficacy cohort.

The result does not mean that the true risk in the Rotarix group is exactly zero. A sample with no observed events can still be compatible with a nonzero underlying risk. Nor does the p-value say that the probability of no difference is below 0.001. It describes evidence relative to a null hypothesis under the analysis assumptions, whose exact method is not reported in the registry record.

The finding concerns one severe, laboratory-identified endpoint during one follow-up interval among participants previously assigned to the two parent-study groups. It does not describe all rotavirus infections, all gastroenteritis, outcomes outside the stated period, or every population that might receive a vaccine. The registry does not establish how the result applies beyond the studied participants and schedules.

The endpoint’s protocol status also matters: it was secondary in the study protocol and is presented as primary in this Year 3 summary because no protocol primary endpoint addressed this follow-up time point. The registry does not report multiplicity procedures or a detailed statistical plan. Statistical evidence should therefore be considered alongside the endpoint’s status, the analysis population, sparse counts, and missing methodological details.

The safety figures are separate descriptive counts. The available numbers do not establish whether any serious adverse event was caused by an intervention, and the record does not report deaths. Neither the efficacy comparison nor these safety summaries provide a complete account of every benefit or harm that might be relevant to a treatment decision.

14. Why This Trial Matters Statistically

This study is statistically notable as a follow-up comparison that focuses on severe wild-type rotavirus gastroenteritis during the third year of life among participants vaccinated earlier in parent studies. Such follow-up asks a different question from an endpoint measured only soon after vaccination: it describes events during a later, defined period. The registry record identifies that period as from Year 2 up to Year 3.

The result also illustrates why outcome definitions and analysis populations matter. The endpoint requires a severe gastroenteritis episode and identification of rotavirus other than the vaccine strain in a stool sample. The efficacy analysis is restricted to the according-to-protocol cohort. Those features define what the comparison represents and also limit the interpretation to the stated endpoint and cohort.

It is useful statistically to distinguish the observed event counts, the absolute risk-difference estimate, and its uncertainty. The counts are sparse, while the estimate and confidence interval communicate the direction and precision of the comparison. The reported p-value adds evidence relative to a null hypothesis but does not replace consideration of the interval, effect scale, or study context.

The registry’s explanation that this endpoint was secondary in the protocol but presented as primary for the Year 3 summary is especially relevant. It shows why a result’s label should be read alongside its follow-up time and protocol role. In addition, the absence of details on multiplicity, missing data, and the precise inferential methods limits how completely the statistical analysis can be evaluated from the registry record alone.

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 registry reports sparse endpoint counts, including no events in the Rotarix efficacy group. Sparse counts make the comparison sensitive to the outcomes observed and mean that the point estimate should not be read in isolation from its confidence interval. The record does not report the interval method, test method, or confidence level, limiting independent assessment of the inferential calculations.

The outcome is described as secondary in the protocol, although it is presented as primary for this summary because the protocol’s primary outcomes did not pertain to this Year 3 time point. The registry record does not report how multiplicity across outcomes was handled, whether the analysis was prespecified, or whether interim analyses were performed. Those details are not reported in the registry record.

The analysis population is the according-to-protocol cohort for efficacy. The registry gives the group counts for this analysis but does not describe exclusions, missing endpoint information, participant flow into the cohort, or missing-data procedures. It also does not provide sufficient detail to assess whether follow-up completeness differed between groups.

The record does not detail severity criteria, laboratory methods, event adjudication, masking roles, or the statistical model. It does not report deaths in the safety summary. The safety risk sets differ from the efficacy group counts, and the adverse-event summary is not a complete account of all event details. These reporting limitations constrain conclusions about reproducibility, generalizability, and the full safety profile.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Year 3 Extension for Efficacy Follow-up in Subjects Vaccinated in Studies Rota-028, 029 or 030 (NCT00197210) — NCT00329745.
• Registry record last updated 2016-12-09; status last verified 2016-10.
• Results first posted 2009-10-14.
• 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

NCT00329745 is a completed Phase III randomized, triple-masked, parallel-group, placebo-controlled, multi-country and multi-center Year 3 extension. Enrollment was 8687. Participants had received two oral doses of Rotarix or placebo in Rota-028, Rota-029 or Rota-030. The listed start is 2007-01 and primary completion is 2008-07.

The efficacy outcome is severe gastroenteritis caused by circulating wild-type rotavirus from Year 2 up to Year 3, analyzed in the according-to-protocol cohort for efficacy. The registry reports 0 events among 4222 Rotarix participants and 13 among 4185 placebo participants. The risk difference is -0.003, with a confidence interval from -0.005 to -0.001 and p < 0.001. The record states that this measure was secondary in the protocol but is presented as primary for this Year 3 summary.

Serious adverse events were reported for separate safety risk sets as 10 among 4359 Rotarix participants and 11 among 4328 placebo participants. Further details on analysis methods, missing data, multiplicity, and deaths are not reported in the registry record.