Safety and Protective Efficacy of Pb(PfCS@UIS4): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Protective Efficacy of Pb(PfCS@UIS4) (NCT03138096), a non-randomized phase 1, phase 2 study. The primary outcome is Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety].

2. Clinical Question

The study rationale was to investigate whether immunization with genetically modified P. berghei could induce a cross-species immune response. The record explains that the parasite was modified to include the P. falciparum circumsporozoite protein gene, and states the hypothesis that immunization could induce that response without the risk of a breakthrough infection. These statements describe the study rationale, not a demonstrated clinical effect.

The registry also lists a challenge infection with P. falciparum as an intervention and ELISA-assessed immunogenicity as a secondary outcome. The primary safety endpoint is narrower: it concerns adverse events following exposure to the modified parasite, with different observation windows for Groups 1 and 2 versus Group 3. The listed endpoint excludes adverse events following challenge infection with wild-type-infected mosquitoes. Numerical results for the primary endpoint and the secondary immunogenicity outcome are not reported in the registry record.

3. Trial Design

This was a Phase 1 and Phase 2, non-randomized, parallel-group study in healthy volunteers. The registry record gives an enrollment of 24, a start date of 2017-05-29, a primary completion date of 2018-03-28, and a completed status. Radboud University Medical Center is listed as the sponsor. The record reports no masking.

The intervention groups were organized around exposure to Pb(PfCS@UIS4)-infected mosquitoes. Group 1 is described as exposure to five infected mosquitoes, and Group 2 as 25 infected mosquito bites. Group 3 is described as 75 infected mosquito bites; its endpoint description specifies four sequential immunizations. The record says Groups 1 and 2 underwent a single immunization. Group 4 is identified as the Phase 1 infectivity control group, and Group 5 as the Phase 2 infectivity control group. The endpoint description specifies that Group 4 did not undergo immunization.

A challenge infection with P. falciparum is also listed. For the primary safety endpoint, adverse events after challenge with wild-type-infected mosquitoes in Groups 3 and 4 were not protocol-defined and are excluded. This distinction matters: the endpoint is not a general account of every event during every study phase.

The record explicitly warns that allocation was non-randomized and that the arms are not a like-for-like control comparison. Differences between groups therefore cannot be read as clean causal contrasts. The registry does not report the allocation procedure, the rationale for group sizes, or detailed statistical planning. Those design details are not reported in the registry record.

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

Analysis population for the primary outcome, as defined in the registry: Groups 1-3, immunization phase only (groups 1\&2 underwent only a single immunization; group 3 underwent 4 sequential immunizations). Note: group 4 did NOT undergo immunization. AEs following CHMI with WT-infected mosquitoes (i.e. in group 3\&4) were not a protocol-defined endpoint and are NOT included here. Group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group.

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.

Population: phase 2 was not effected

6. Primary Endpoint

The registry lists the primary outcome as Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety], measured over Groups 1&2: from exposure to Pb(PfCS@UIS4)-infected mosquitoes until 28 days thereafter. Group 3: from first exposure until 21 days after fourth/final exposure (=until day immediately prior to CHMI, i.e. approximately 15 weeks after first exposure)..

The primary endpoint is titled as adverse events in study groups following exposure to Pb(PfCS@UIS4)-infected mosquitoes, under the safety domain. It is described as measuring the frequency and magnitude of adverse events. The stated unit is numbers of adverse events, so the endpoint is intended to characterize event burden, rather than only whether a participant experienced any event.

The endpoint applies to Groups 1–3 during the immunization phase. Its observation window differs by group: for Groups 1 and 2, it runs from exposure until 28 days thereafter. For Group 3, it runs from the first exposure until 21 days after the fourth or final exposure, immediately before challenge infection; the record describes this as approximately 15 weeks after the first exposure. Adverse events following challenge with wild-type-infected mosquitoes in Groups 3 and 4 are not included in this protocol-defined endpoint.

Safety endpoints are used to describe undesirable events observed in a trial and their timing and magnitude. General statistical context: event counts can convey more information than a simple affected/not-affected summary, but interpretation depends on clear definitions, observation time, and whether the count refers to events or participants. Although the registry gives the endpoint unit as adverse-event numbers, the posted results needed to characterize those counts are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods for the primary endpoint are not reported in the registry record. The record identifies a count-type endpoint, but it does not state the analysis model, whether counts were compared between groups, how repeated events were handled, or how uncertainty was quantified. It also lists zero analyses. Without those details and the endpoint results, a model-based estimate or inferential conclusion cannot be reconstructed.

What does an adverse-event count represent?

General statistical explanation: a count endpoint records how many events occur in a defined observation period. It differs from a participant-level indicator that records whether a person experienced any event. One participant may contribute more than one event, depending on the endpoint definition. For that reason, an event count and the number of affected participants are not interchangeable. The registry names the primary endpoint unit as numbers of adverse events, while the separately listed safety fields describe numbers at risk and numbers affected. The record does not provide enough detail to reconcile those summaries with the complete primary endpoint count.

For count data, interpretation depends on exposure time and the opportunity to experience an event. General statistical explanation: if observation periods differ, a raw count may reflect both event occurrence and time under observation. The registry specifies different primary-endpoint windows for Groups 1 and 2 and Group 3. It does not report a rate analysis or explain how the differing windows were handled statistically. Readers should therefore avoid treating counts from those groups as directly comparable rates.

Why can count data need specialized models?

General statistical explanation: count outcomes are often analyzed with models that account for their non-negative, discrete nature. A simple count model may be inadequate when event counts vary more than the model expects, a condition called over-dispersion. In that situation, standard errors from an overly restrictive model can be too small, making uncertainty appear less than it is. Other features, such as repeated events within participants or unequal follow-up, can also affect the choice of model. The registry does not say whether over-dispersion, repeated events, or exposure time were assessed, and it does not identify any model used.

Confidence intervals, when reported, describe the range of estimates compatible with a statistical procedure and its assumptions; they communicate precision as well as the estimated value. General statistical explanation: a broad interval indicates substantial uncertainty, while a narrow interval indicates greater precision under the stated method. No confidence interval for the primary endpoint is reported in the registry record. No p-value or group contrast for that endpoint is reported either.

What can the planning illustrations tell readers?

The record describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the illustrations vary the effect to detect as a stated fraction of the observed effect. These are planning illustrations, not observed trial results or observed power. The numerical planning outputs and the magnitude of the observed effect are not reported in the registry record, so their implications cannot be assessed from the record alone.

General statistical explanation: planning calculations depend on assumptions about the effect worth detecting, outcome variability, allocation, and the statistical test. A calculation based on an effect observed in the same study does not establish that the study was adequately designed in advance to detect a clinically meaningful effect. The registry does not report a sample-size justification or the assumptions used for the original trial design.

How should group comparisons be viewed?

The allocation is non-randomized, and the registry expressly says the arms are not a like-for-like control comparison. General statistical explanation: random allocation can help balance known and unknown characteristics between groups, whereas non-random allocation may leave group differences associated with outcomes. Statistical adjustment can sometimes address measured differences, but it cannot guarantee removal of bias from unmeasured factors. The registry does not report an adjusted analysis, a covariate set, or a method for addressing confounding. No causal interpretation should be inferred from unadjusted group summaries.

The registry lists six outcome measures, but only the ELISA-assessed immunogenicity outcome is identified in the secondary-outcome description. It does not report the statistical procedures for that outcome or how its results relate to the safety endpoint. The record therefore supports a description of the intended questions, but not a reconstruction of the analytical plan or a quantitative assessment of precision.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and identifies ELISA-assessed immunogenicity as a secondary outcome. It does not report a multiplicity strategy, such as how interpretation would account for examining several outcomes or making multiple comparisons. That strategy is not reported in the registry record. Without it, the intended control of false-positive findings across outcomes cannot be evaluated.

Missing-data procedures are also not reported. The record does not state whether outcome data were complete, how unavailable observations were handled, whether participants were excluded from particular analyses, or whether sensitivity analyses were conducted. The lack of reported analysis details does not establish that data were complete or that missingness had no effect.

The analysis populations are not defined in the registry record. It does not specify whether participants were analyzed according to exposure received, protocol adherence, or another population definition. Nor does it report exclusions or the number analyzed for each endpoint. The listed safety fields include numbers at risk for Groups 1–4, but these entries alone do not define an analysis population or resolve missing outcome information.

The registry reports zero analyses. As a result, multiplicity handling, missing-data assumptions, and analysis-population definitions cannot be checked against reported statistical results. These gaps limit assessment of both the reliability and the intended interpretation of the outcomes.

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 non-serious adverse event terms

The serious-event fields list zero participants affected in Group 1, Group 2, Group 3, and Group 4. The death field lists zero in each of those groups. The registry also identifies the numbers at risk for these fields: 3 for Group 1, 3 for Group 2, 12 for Group 3, and 6 for Group 4. These are group-specific entries; they should not be added together to create a new total.

These serious-event entries are not the primary endpoint results. The primary endpoint concerns the frequency and magnitude of adverse events during the immunization phase in Groups 1–3, and the registry does not report its numerical results. The safety fields also list other adverse events affecting participants, but they do not provide full event-level descriptions in the record. Group 4 is an infectivity control group and did not undergo immunization, so its entry should not be interpreted as an immunized comparison arm.

A zero in the serious-event field describes the reported serious-event count for that group; it does not establish that no non-serious events occurred, nor does it establish the absence of risk beyond the observation period. The registry does not provide detailed serious-event terms; its top serious-event terms list is empty.

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

The record documents a study of safety and protective efficacy involving genetically modified Pb(PfCS@UIS4) parasites in healthy volunteers. Its stated rationale is to explore whether immunization with modified P. berghei could induce a cross-species immune response, with a P. falciparum circumsporozoite protein gene included in the parasite. That rationale and hypothesis are not themselves evidence that the intended immune response occurred or that protection was achieved.

The posted record does not report numerical results for the primary adverse-event endpoint, and it reports zero analyses. It also does not report numerical results for the ELISA-assessed immunogenicity outcome. Therefore, the record cannot support a quantitative conclusion about the frequency or magnitude of the primary safety outcome, immunogenicity, or protective efficacy. The listed zero serious adverse events and zero deaths are limited entries and do not replace those missing outcome results.

The study is non-randomized, and the registry warns that its arms are not a like-for-like control comparison. Differences between groups would therefore need careful interpretation even if complete outcome summaries were available. Group exposure levels and observation windows also differ, and the primary safety endpoint excludes events following the later challenge with wild-type-infected mosquitoes.

General statistical explanation: a study’s design and stated hypothesis describe what investigators set out to examine; conclusions depend on the results, their precision, and the limits of the design. Here, outcome estimates and uncertainty for the primary endpoint are not reported in the registry record. The record should be read as documenting the trial framework and selected safety counts, not as establishing the presence or absence of a clinical benefit or a complete safety profile.

13. Why This Trial Matters Statistically

This trial raises statistical issues that are important when interpreting early studies of biological interventions. The primary endpoint is a count of adverse events, while the separately listed safety figures include affected participants. Distinguishing events from people affected is essential: repeated events may contribute differently from a participant-level summary, and the record does not give enough detail to equate those measures.

The endpoint’s observation windows differ across the immunization groups. General statistical explanation: comparisons of raw counts can be difficult when groups have different periods of observation, because the opportunity to record an event may differ. A clear analysis would need to explain how that feature was handled. The registry does not report such a method or the primary endpoint results.

The non-randomized allocation is another important constraint. The registry itself cautions that the arms are not a like-for-like control comparison. This limits the interpretation of between-group differences as evidence of an intervention effect, particularly when exposure groups and control groups have different roles in the study.

Finally, the record illustrates why reporting the analysis population, handling of missing data, statistical methods, estimates, and uncertainty matters. The serious-event and death entries are useful but narrow; they cannot answer the broader primary safety question. The registry describes a potentially informative research question, but the reported information is insufficient to assess the primary endpoint statistically or to draw conclusions about protective efficacy.

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 is that numerical results for the primary endpoint are not reported in the registry record. Although safety fields list serious adverse events, other adverse events, and deaths, those entries do not provide the primary endpoint’s event frequency and magnitude. The record also reports zero analyses, so estimates, uncertainty measures, and inferential comparisons are unavailable.

The design was non-randomized, and the registry explicitly cautions that the arms are not a like-for-like control comparison. Group 4 did not undergo immunization, while Groups 1–3 had differing exposure schedules. These features complicate direct comparisons. The record does not report adjustment methods or other steps to address group differences.

Observation periods vary for the primary safety endpoint: Groups 1 and 2 are followed until 28 days after exposure, while Group 3 is followed through 21 days after its final exposure, approximately 15 weeks after the first exposure. The registry does not report a statistical method for accounting for these differing windows. It also excludes adverse events after challenge with wild-type-infected mosquitoes in Groups 3 and 4, limiting the scope of the endpoint.

Other limitations include the absence of reported analysis populations, missing-data procedures, multiplicity handling, endpoint analysis methods, and numerical immunogenicity results. The serious-event terms are not detailed. These omissions prevent a fuller assessment of the safety findings, precision, and potential biases from the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Protective Efficacy of Pb(PfCS@UIS4) — NCT03138096.
• Registry record last updated 2022-03-04; status last verified 2017-03.
• Results first posted 2021-12-15.
• 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

The registry record describes NCT03138096, a completed, non-randomized Phase 1 and Phase 2 parallel-group study sponsored by Radboud University Medical Center. Enrollment was 24. The study examined genetically modified Pb(PfCS@UIS4) parasite exposure in healthy volunteers, with groups defined by infected-mosquito exposure and infectivity control groups.

The primary endpoint was adverse-event frequency and magnitude after exposure to Pb(PfCS@UIS4)-infected mosquitoes during specified immunization-phase windows. ELISA-assessed immunogenicity was identified as a secondary outcome. The record lists zero serious adverse events affecting participants and zero deaths in Groups 1–4, but numerical results for the primary endpoint and immunogenicity outcome are not reported. The record reports zero analyses and cautions that the non-randomized arms are not a like-for-like control comparison.