Double-blind, Randomized, Controlled Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Double-blind, Randomized, Controlled Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine (NCT00223990), a randomized phase 2 study. The primary outcome is Subjects Time to First Clinical Episode of P Falciparum Malaria During the Efficacy Follow-up Period Adjusted for Time at Risk - Intent to Treat (ITT) Population.

2. Clinical Question

The trial was designed to assess safety, immunogenicity, and efficacy. The primary outcome is framed around the first clinical malaria episode, with time at risk adjusted for study absence and malaria treatment. The case definition for the primary endpoint requires fever above 37.5°C and asexual P. falciparum density above 50K parasites/µL blood. Several alternative case definitions are also described in the registry, using different parasite-density thresholds or, for one definition, a history of fever in the last 24 hours.

The registry’s summary says the study investigates whether the candidate vaccine prevents malaria disease for 6 months post-vaccination. That statement describes the study question, not a reported finding. A comparative estimate, uncertainty interval, or statistical test for the primary outcome is not reported in the registry record, so the clinical question cannot be answered from the posted results alone.

3. Trial Design

This was a randomized, double-blind, parallel-group, phase II field trial. It enrolled 400 children aged 12-47 months in western Kenya and compared FMP1/AS02A with RabAvert, a rabies vaccine. The record lists the study as completed. The recorded start date is 2005-04-08, and the primary completion date is 2006-04-26.

Both assigned vaccines were administered intramuscularly in the left anterolateral thigh at 0, 1, and 2 months. The registry summary describes one half of the enrolled subjects as receiving FMP1/AS02A and the other half as receiving RabAvert. Random allocation supports a comparison of assigned groups, while double masking is intended to reduce the influence of knowledge of assignment on participant experience, clinical assessment, and related decisions. The registry record does not report further details about how randomization or masking was implemented.

The study aimed to evaluate efficacy, safety, and immunogenicity. The primary outcome concerns time to first clinical episode of P falciparum malaria during efficacy follow-up, adjusted for time at risk. Its stated observation period begins 14 days after the third vaccination, identified as day 71, with assessments every 28 days and follow-up ending on day 240. The record also lists secondary outcomes concerning time to first malaria episode, solicited symptoms, unsolicited adverse events, and serious adverse events. No immunogenicity outcome details are included in the posted results.

The protocol, sample-size justification, detailed allocation procedures, and statistical analysis plan are not reported in the registry record. The record lists no analysis entries. Thus, although the trial design establishes the intended comparison and outcome framework, the available information does not establish which statistical models, covariate adjustments, censoring rules, or decision thresholds were ultimately applied.

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 Subjects Time to First Clinical Episode of P Falciparum Malaria During the Efficacy Follow-up Period Adjusted for Time at Risk - Intent to Treat (ITT) Population, measured over starting 14 days after the 3rd vaccination (day 71), every 28 days and ending on day 240.

The primary endpoint concerns the time until a participant’s first clinical episode of P falciparum malaria during efficacy follow-up, with time at risk adjusted for study absence and malaria treatment. Time-to-first-event outcomes use both whether an event occurred and when it occurred. They can therefore distinguish an event early in follow-up from one occurring later, rather than treating all affected participants as if their event timing were identical.

The registry describes the primary case definition as fever above 37.5°C together with asexual P. falciparum density above 50K parasites/µL blood. It also lists alternative definitions, including thresholds above 200K, 100K, 10K, and 0 parasites/µL blood, as well as a definition allowing either fever or a history of fever in the last 24 hours with detectable parasites. These definitions represent different rules for identifying a clinical episode; they should not be treated as interchangeable without knowing which analysis was prespecified for each purpose.

Accounting for time at risk is relevant when participants do not contribute the same amount of observed time. The record identifies study absence and malaria treatment as factors in that adjustment, but does not describe the exact calculation or handling of those periods. The primary outcome is labelled as a number of events in the registry, while its title and description refer to time to first episode. A comparative endpoint estimate and its uncertainty are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General: A randomized comparison evaluates outcomes in groups formed by assigning participants to interventions by chance. Randomization is intended to balance measured and unmeasured prognostic factors across groups on average, rather than to ensure identical groups in every trial. This study is recorded as randomized, double-blind, and parallel-group. The registry does not report the randomization sequence method, concealment procedure, or details of who remained masked.

What does a time-to-event outcome measure?

General: Time-to-event methods use the timing of an event as well as whether it occurred during observation. They can accommodate participants whose observed follow-up differs, provided the analysis defines how incomplete observation is handled. In this trial, the event of interest is the first clinical episode of P falciparum malaria, and the registry says time at risk is adjusted for study absence and malaria treatment. The precise method for this adjustment is not reported in the registry record.

A time-to-first-event analysis ordinarily focuses on the first qualifying episode for each participant, rather than counting repeated episodes as separate primary events. The registry’s primary outcome title and description refer to time to first episode, but its measurement label is “NUMBER” with the unit “events.” The record does not explain this presentation or provide a group-specific endpoint result. The follow-up window is described as starting 14 days after the third vaccination (day 71), with assessments every 28 days and ending on day 240.

Why do event definitions matter?

General: An outcome definition determines which observations count as events. A stricter threshold may identify a different set of cases than a more inclusive threshold, so results based on different definitions answer different operational questions. The registry specifies fever above 37.5°C and parasite density above 50K parasites/µL blood for the primary case definition. It also lists secondary definitions using above 200K, 100K, 10K, and 0 parasites/µL blood, plus a definition that allows fever or a history of fever in the last 24 hours with parasite density above 0 parasites/µL blood. The record does not provide the comparative results for these definitions.

How should precision be assessed?

General: A point estimate alone describes the observed contrast, while an uncertainty interval communicates how much precision the data support under the chosen statistical method. A confidence interval is commonly interpreted as a range of effect values reasonably compatible with the data and model assumptions. A p-value addresses compatibility of the data with a specified null hypothesis under a statistical model; it does not measure the size or clinical importance of an effect. The registry record does not report a primary-outcome estimate, confidence interval, or p-value, so these measures cannot be interpreted for the primary comparison.

For event counts, uncertainty depends on the number of events and the analysis approach. When event rates vary more than a simple model expects, over-dispersion can make standard errors too small if it is ignored; methods that account for extra variability can yield more cautious uncertainty estimates. This is general statistical context only: the primary endpoint is described as time to first event, and the registry record does not identify an over-dispersion assessment or a model used for the posted endpoint.

What can planning calculations tell us?

General: Sample-size calculations use assumptions about the target effect, variability or event frequency, significance level, allocation, and desired power. A planning illustration asks how many participants or events a hypothetical design would require under specified assumptions. It is not the same as the number enrolled, and it does not show the probability that a completed trial detected an effect. The planning assumptions described for the calculations associated with this record use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Time-to-event illustrations use a total event count; other illustrations use participants per arm. These are planning illustrations, not observed power, and the registry does not report the trial’s own sample-size justification.

General: A recalculation from posted summary statistics, when one is available, is an unadjusted reconstruction and may not reproduce a sponsor’s prespecified analysis. In the present registry record, there is no posted primary-outcome comparison from which to interpret such a reconstruction. The record lists no analysis entries, and no statistical model, adjustment set, censoring approach, or interim analysis plan is reported. Any explanation of those methods would therefore be speculation and is not appropriate.

10. Multiplicity, Missing Data and Analysis Populations

The record lists a primary outcome and multiple secondary outcomes. These include time to first clinical episode in the according-to-protocol population, vaccine-related solicited symptoms, unsolicited adverse events, and serious adverse events, with some safety outcomes described for both intent-to-treat and according-to-protocol populations. It also lists several alternative malaria case definitions. Looking at many outcomes or definitions can increase the chance of finding at least one apparently notable result by chance when each is tested separately. General statistical practice may address this through prespecification, hierarchical testing, or adjustment for multiple comparisons, but the registry record does not report a multiplicity strategy.

The record identifies the primary outcome population as intent-to-treat and lists several secondary safety outcomes in both intent-to-treat and according-to-protocol populations. In general, intent-to-treat analyses compare participants according to randomized assignment, while according-to-protocol analyses apply protocol-defined eligibility or adherence criteria. These populations can answer different questions and can produce different estimates. The exact population definitions and analysis counts are not reported in the registry record, so the consequences of exclusions or protocol deviations cannot be assessed.

Missing outcome data and incomplete follow-up can affect time-to-event analyses, especially when the reasons for loss of observation are related to outcome risk. The registry describes adjustment for study absence and malaria treatment, but does not report the amount or pattern of missing data, how censoring was handled, or whether sensitivity analyses were conducted. These details are not reported in the registry record. The record also does not report an interim-analysis plan or stopping rules. Without these details, it is not possible to determine how multiplicity, missingness, or analysis-population choices were handled in the final statistical analysis.

11. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: parasitemia >20% (4.5%), cellulitis (1.0%), pneumonia (1.0%), cerebral malaria; severe anemia (0.5%), convulsions (0.5%).

The registry lists 200 participants at risk for serious adverse events in each group. It records serious adverse events in 15 participants in the FMP1/AS02A group and 8 in the RabAvert group. For other adverse events, the listed figures are 197 of 200 in each group. Deaths are recorded for 1 participant in the FMP1/AS02A group and 0 in the RabAvert group.

These counts describe the safety information posted in the registry; they are not, by themselves, adjusted comparisons or evidence of causation. The record does not provide confidence intervals, statistical tests, event-level timing, or a description of how relatedness was adjudicated for these group summaries. It also does not clarify whether one participant could contribute more than one event to every listed category. The term “vaccine-related” appears in the titles of some secondary outcomes, but the group-level totals above are not presented as a detailed analysis of causality.

The registry lists several serious-event terms and percentages, including Parasitemia >20% at 4.5%. The listed summary does not assign those terms to a randomized group. They should not be read as a complete breakdown of serious events by intervention. The safety counts are useful descriptive information, but a fuller comparison would require the event definitions, follow-up, attribution, and uncertainty measures, which are not reported in the registry record.

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

The study record establishes that a randomized, double-blind comparison of FMP1/AS02A and RabAvert was conducted in children in western Kenya, with a primary outcome based on time to first clinical episode of P falciparum malaria. It also reports selected adverse-event counts for the two groups. These details describe the design and the recorded safety summaries; they do not, on their own, establish the comparative efficacy or safety of the candidate vaccine.

The registry does not report the primary-outcome results by group, a treatment contrast, or an uncertainty interval. It is therefore not possible to state from this record whether the observed time to first malaria episode differed between groups, how large any difference was, or how precisely it was estimated. The absence of a posted estimate must not be interpreted as evidence of no difference. Conversely, the study’s stated purpose of evaluating prevention does not demonstrate that prevention was achieved.

The serious adverse-event counts and death counts are descriptive. Differences in counts may reflect chance, underlying risk, exposure time, data collection, or other factors; comparative inference would require an appropriate analysis and its assumptions. The registry does not provide the statistical detail needed to distinguish among these possibilities. Nor does it report a full accounting of missing follow-up or the analysis populations contributing to each outcome.

General: Clinical trial interpretation separates the design question from the result and separates an observed estimate from the certainty around it. An outcome can be measured without the posted record containing enough information to interpret its between-group contrast. Here, the registry offers the endpoint definition and selected safety counts, but not the main comparative efficacy result or its precision. The evidence described in the record should therefore be understood as incomplete for judging the primary statistical question.

13. Why This Trial Matters Statistically

This trial is statistically notable for the structure of its main question: a randomized comparison of time to first clinical malaria episode, with an adjustment for time at risk. This type of endpoint combines event occurrence with event timing and requires clear rules for defining an episode, accounting for observation time, and handling participants whose follow-up is incomplete. The registry describes several alternative case definitions, making clarity about which definition is primary and how the alternatives are interpreted especially important.

The record also illustrates why a trial’s design and its result are not the same thing. Randomization and masking describe features intended to support a fair comparison, but they do not replace a reported effect estimate and its uncertainty. The registry identifies a primary endpoint and an intent-to-treat population, yet does not include the group-specific primary outcome results or an inferential analysis. This limits statistical interpretation even though the trial status is completed.

The safety entries also demonstrate the distinction between descriptive counts and comparative evidence. Counts of participants with events can help characterize what was recorded, but their interpretation depends on outcome definitions, time under observation, event attribution, and uncertainty. The registry lists serious adverse events and deaths by group, while leaving important analytical details unreported.

For clinical researchers, the record underscores the value of transparent reporting of analysis populations, missing-data handling, multiplicity plans, and precision estimates. Those details allow readers to understand not just what outcome was intended, but how the final comparison was constructed and how much uncertainty remains. In this case, the protocol-level statistical details and primary comparative result are not reported in the registry record.

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 important limitation for interpretation is that the registry record does not report a primary-outcome comparison. It identifies the time-to-first-malaria endpoint and its case definition, but gives no group-specific estimates, contrast, confidence interval, or p-value. The posted results therefore do not permit an assessment of the direction, magnitude, or precision of the primary efficacy result.

The record’s primary outcome label describes a number of events, while the title and definition describe time to first episode. It does not explain how that presentation relates to the analysis or provide event counts by group. The time-at-risk adjustment is said to account for study absence and malaria treatment, but the calculation and handling of these periods are not reported. The endpoint timeframe and alternative case definitions are described, but their comparative results are not included.

Safety information is also limited in detail. The registry provides participant counts for serious and other adverse events and deaths, but does not report uncertainty estimates, event-level timing, the full event definitions, or a group-specific breakdown of the listed serious-event terms. The criteria and process for assessing vaccine relatedness are not detailed in the posted summary.

The record does not report the protocol, sample-size justification, statistical analysis plan, missing-data approach, analysis population definitions, interim analyses, or multiplicity strategy. It lists intent-to-treat and according-to-protocol populations for different outcomes, but does not give outcome-specific analysis counts. As a result, readers cannot determine how exclusions, incomplete follow-up, or protocol deviations affected the final analyses. These omissions limit interpretation of the registry results; they do not establish that the trial lacked such procedures, only that they are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Double-blind, Randomized, Controlled Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine — NCT00223990.
• Registry record last updated 2021-02-12; status last verified 2021-02.
• Results first posted 2020-05-21.
• 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

NCT00223990 is a completed, randomized, double-blind, parallel-group phase II trial of FMP1/AS02A versus RabAvert in children in western Kenya. The registry records enrollment of 400 and lists study dates of 2005-04-08 and 2006-04-26 for start and primary completion.

The primary outcome is time to first clinical episode of P falciparum malaria during efficacy follow-up, adjusted for time at risk, in the intent-to-treat population. The record describes a primary fever and parasite-density definition alongside alternative definitions. It also lists safety outcomes and secondary analyses in intent-to-treat and according-to-protocol populations.

Posted safety counts include serious adverse events in 15 of 200 participants receiving FMP1/AS02A and 8 of 200 receiving RabAvert, and deaths of 1 and 0, respectively. A comparative primary-outcome estimate, its uncertainty, and detailed analysis methods are not reported in the registry record.