Trial to Evaluate L9LS in Healthy Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial to Evaluate L9LS in Healthy Adults (NCT05019729), a non-randomized phase 1 study. The primary outcome is Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration.

2. Clinical Question

3. Trial Design

This completed phase 1 study evaluated L9LS in healthy malaria-naive adults. The registry record describes it as dose-escalation, open-label, non-randomized and sequential. Enrollment was 32. The study started on 2021-09-13, and primary completion was recorded as 2022-09-19.

Participants were assigned to six groups. Three received L9LS by intravenous infusion: 1 mg/kg, 5 mg/kg or 20 mg/kg. A group received 5 mg/kg by subcutaneous injection, and another received 5 mg/kg by intramuscular injection. A CHMI control group did not receive L9LS. The registry record says the intramuscular group was enrolled after CHMI and did not take part in the challenge.

The study included controlled human malaria infection with a Plasmodium falciparum sporozoite challenge. The registry record lists the number of participants developing parasitemia after challenge as a secondary outcome, but does not report those results. It also lists pharmacokinetic measures, including maximum serum concentration, time to maximum concentration, beta half-life, clearance and volume of distribution, with routes specified for some measures. Their numerical results are not reported in the registry record.

Participants who received L9LS were monitored for side effects, with follow-up visits and diary-card reporting described in the record. The primary endpoint concerns local reactogenicity during the seven days after administration. Because allocation was non-randomized and the design was open-label, observed differences between groups would not by themselves establish that L9LS caused a difference. The registry record does not report the sequence or rules used for dose escalation, nor a detailed statistical plan.

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: Population included all enrolled participants who received L9LS and had safety data collected via diary card (N=23). Group 5 CHMI controls did not receive L9LS.

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: Population included all enrolled participants. Age represents age at enrollment day. Weight represents weight from enrollment evaluation for participants who received L9LS.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration, measured over 7 days after L9LS product administration, at approximately Week 1.

The primary endpoint is the number of participants reporting local reactogenicity signs and symptoms within seven days of L9LS administration, at approximately Week 1. Participants recorded solicited symptoms on a diary card and reviewed it with clinic staff at follow-up. If a participant reported a symptom more than once or at more than one severity, the record counted that participant once for that symptom at the worst reported severity. The measure labelled Any Local Symptom counts participants who reported at least one local symptom, also using the worst severity.

This is a count of participants, not a count of symptom episodes. That distinction matters because repeated reports by one participant do not add multiple participants to the endpoint. The registry record says severity grading used the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.

In general, a solicited reactogenicity endpoint records prespecified symptoms during a defined period after administration. Such an endpoint can describe the frequency and severity of reported local symptoms in the monitored population. It does not, on its own, establish whether an event was caused by the study product, and it is distinct from an endpoint measuring protection against infection. The registry record identifies the primary endpoint population as L9LS recipients with diary-card safety data (N=23); the outcome counts by symptom and severity are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a non-randomized, open-label, sequential phase 1 study and lists outcome measures, but does not report inferential analyses or a detailed statistical analysis plan. The explanations below describe general statistical concepts relevant to the design; they do not assert that a particular unreported method was used.

What does a participant count describe?

A participant count records how many people met an outcome definition during the specified observation period. For the primary endpoint, each participant is counted once for a given symptom, at the worst severity they reported. This differs from counting every occurrence: one person with repeated reports still contributes one participant to that symptom’s count. A count is most informative when its population, observation window and outcome definition are clear. The registry specifies a seven-day window after L9LS administration and identifies the diary-card population as N=23, but does not report the symptom-specific counts.

Counts are descriptive. A count alone does not show how uncertain an underlying event frequency may be, and a count across groups does not establish a causal difference. General statistical practice often presents a count together with its denominator and, where appropriate, an interval estimate. An interval communicates the range of values reasonably compatible with the data under the method’s assumptions. The primary endpoint’s detailed counts and any associated interval estimates are not reported in the registry record.

Why does the allocation method matter?

In general, randomization assigns participants by chance and can reduce systematic differences between groups at baseline. Here, allocation is recorded as non-randomized, and the study is described as sequential. Thus, comparisons between dose groups may be influenced by differences in who entered each group, when groups were enrolled, or other factors. Those are general concerns for non-randomized comparisons, not claims about imbalances that occurred in this study; baseline balance information is not reported in the registry record.

Open-label means masking is recorded as none. In general, knowledge of the assigned intervention can influence reporting, care, or assessment, especially for subjective symptoms. Diary cards and defined grading criteria provide a structured way to collect symptom information, but do not remove every potential source of reporting or assessment variation. The record describes diary-card collection and a grading reference; it does not report whether assessors applied any additional masking or validation procedures.

How should a planning illustration be read?

The registry record describes planning illustrations computed from the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The target effect is described as a stated fraction of the observed effect. In general, a sample-size calculation estimates how many participants would be needed under chosen assumptions to target a specified statistical power for detecting a defined effect. Changing the effect size, variability, allocation or analysis assumptions changes the illustration.

These planning illustrations are not a report of the study’s actual prospective sample-size justification. They are also not observed power. Observed power calculated from an effect estimated in the same data does not add an independent measure of evidence; the observed estimate and its uncertainty are more informative. The numerical planning results and the prospective sample-size justification are not reported in the registry record.

What can be learned from the listed outcomes?

The registry lists secondary outcomes for parasitemia after CHMI and pharmacokinetic parameters. In general, pharmacokinetic summaries describe how drug concentration changes over time and how the body distributes or clears a drug. The listed parameters include maximum observed serum concentration, time to that maximum, beta half-life, clearance and volume of distribution, with intravenous and non-intravenous measures identified separately where relevant. Listing an outcome does not mean its numerical result is available. Those results are not reported in the registry record.

For a binary outcome, the basic descriptive result is the number of participants experiencing the event within the defined population and observation period. Statistical comparison requires a clearly defined contrast and an analysis method that reflects the design. Since no analyses are listed in the registry record, no model, adjustment strategy, hypothesis test or confidence-interval method can be attributed to the trial. The registry record also does not report an approach to over-dispersion; in general, over-dispersion refers to greater variability than a model assumes and can make standard uncertainty estimates too small if not addressed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 15 outcome measures, including the primary local-reactogenicity measure and secondary outcomes related to CHMI parasitemia and pharmacokinetics. When a study examines multiple outcomes or makes multiple comparisons, the chance of at least one apparently unusual result can increase. In general, a prespecified multiplicity strategy may control that chance or distinguish a primary confirmatory question from exploratory analyses. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a plan for interpreting multiple comparisons. It also does not report inferential analyses.

Missing-data handling is not reported in the registry record. The primary endpoint population is described as enrolled participants who received L9LS and had safety data collected via diary card (N=23), but the record does not state whether any otherwise eligible diary data were incomplete, how incomplete diaries were treated, or whether participants were excluded from particular symptom summaries. Without that information, the extent and possible influence of missing endpoint data cannot be assessed.

The registry record identifies the primary endpoint population, but detailed analysis populations for the CHMI and pharmacokinetic outcomes are not reported. In general, an analysis population defines which participants contribute to a particular result; different outcomes can have different eligible populations and observation requirements. The record does not report rules for protocol deviations, withdrawals, or missing challenge or pharmacokinetic measurements. These omissions limit assessment of whether the reported safety counts represent all eligible observations and how secondary results would have been analyzed.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry record reports serious adverse-event counts separately for each group. The counts of participants with a serious adverse event were zero in Group 1: L9LS (1 mg/kg IV), among 5 at risk; zero in Group 2: L9LS (5 mg/kg IV), among 4 at risk; zero in Group 3: L9LS (5 mg/kg SC), among 5 at risk; zero in Group 4: L9LS (20 mg/kg IV), among 4 at risk; zero in Group 5: CHMI Controls, among 6 at risk; and zero in Group 6: L9LS (5 mg/kg IM), among 5 at risk. Deaths were recorded as zero in every group.

These are observed counts, not proof that serious adverse events are impossible or that the groups have identical safety. The group sizes are small, and the study was non-randomized. The record also reports participants affected by other adverse events: 4 in Group 1, 3 in Group 2, 5 in Group 3, 0 in Group 4, 1 among CHMI controls, and 2 in Group 6. Those counts are descriptive and do not establish causation or a dose-response pattern. The registry record does not provide event terms for these other adverse events in the listed summary.

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

The registry record documents a completed early-phase study of L9LS in healthy malaria-naive adults, with several routes and dose levels, a CHMI control group, and a primary endpoint focused on local reactogenicity. It also records serious adverse-event and death counts by group. This information describes the study structure and selected safety observations, but does not provide the primary symptom counts or results for the challenge and pharmacokinetic outcomes.

Accordingly, the record does not allow a reader to quantify the frequency or severity of local symptoms from the primary endpoint. It also does not provide the reported parasitemia results needed to assess the CHMI outcome, or numerical pharmacokinetic results. The stated study objective includes evaluating safety and protective efficacy, but an objective is not itself evidence of an outcome. No conclusion about protection from malaria infection can be drawn from the results reported in the registry record.

In general, a small phase 1 study can provide descriptive information about safety observations and drug handling in the participants studied. It is not, by design alone, proof of benefit or a complete account of uncommon harms. Here, the non-randomized and open-label design also limits causal interpretation of differences between groups. The zero serious adverse-event counts are observations within the recorded groups, not a guarantee about future participants.

The registry record does not report confidence intervals, hypothesis tests or a detailed statistical analysis plan. Therefore, precision and statistical uncertainty for the primary endpoint and secondary outcomes cannot be evaluated from the reported information. The record also does not report a prospective sample-size justification. Any planning illustration based on an observed effect should be read as a planning exercise, not as observed power or as evidence that a particular effect was established.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that are central to interpreting early clinical research. First, the primary endpoint is a participant-level count of solicited local symptoms over a defined seven-day period. Clear definitions of the population, window, severity grading and counting rule help distinguish the number of affected participants from the number of symptom episodes. The registry record gives those definitions, while the symptom-specific results are not reported there.

Second, the dose and route groups were non-randomized and sequential. In general, the comparison of groups depends not only on the intervention but also on how participants enter each group and on the timing and conduct of observation. That makes descriptive presentation and restraint in causal claims especially important. The CHMI control group has a specific role in the challenge design, but does not create a randomized control comparison for the L9LS safety groups.

Third, the study has several distinct questions: local tolerability, parasitemia after controlled infection, and pharmacokinetics. These outcomes use different measurements and may involve different analysis populations. Reporting the outcome definitions alongside their results is necessary for readers to judge what each result says. The registry record lists the outcomes but does not report the primary counts, challenge results or pharmacokinetic values.

Finally, the serious adverse-event summary illustrates why safety counts need their denominators and study context. Zero recorded serious events in these groups is a useful descriptive observation, but not a precise estimate of safety in a wider population. In general, uncertainty intervals and transparent reporting of missing observations would help readers assess precision. Those details 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 principal limitation for interpreting results is that the registry record does not report the primary endpoint counts by symptom or severity. It therefore does not support a quantitative account of local reactogenicity, despite describing how the endpoint was collected and graded. The secondary CHMI parasitemia and pharmacokinetic outcomes are listed, but their numerical results are not reported in the registry record either.

The design was non-randomized, open-label and sequential. These features limit the strength of comparisons across groups: group differences can reflect factors other than dose or route, and symptom reporting may be influenced by knowledge of assignment. The record does not report baseline characteristics by group, so comparability cannot be assessed. The CHMI control group did not receive L9LS, while the intramuscular group was enrolled after CHMI and did not participate in it; their roles therefore differ by outcome.

The primary endpoint population is specified as L9LS recipients with diary-card safety data (N=23), but the registry record does not report whether diary data were missing or how missing observations were handled. It also does not report analysis populations for each secondary outcome, a multiplicity strategy, inferential methods, confidence intervals or a detailed statistical plan. Prospective sample-size justification is not reported in the registry record; planning illustrations based on an observed effect do not fill that gap.

Finally, the group-specific serious adverse-event counts are descriptive and based on the recorded participants at risk. They cannot rule out uncommon harms or establish differences between groups. The registry record’s brief summary is truncated during its description of the challenge procedure, so further procedural details are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Trial to Evaluate L9LS in Healthy Adults — NCT05019729.
• Registry record last updated 2024-08-14; status last verified 2024-07.
• Results first posted 2023-10-13.
• 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

NCT05019729, titled Trial to Evaluate L9LS in Healthy Adults, is recorded as a completed phase 1 study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Enrollment was 32. The study began on 2021-09-13, with primary completion on 2022-09-19. It was non-randomized, open-label and sequential.

The six groups covered intravenous L9LS at 1 mg/kg, 5 mg/kg and 20 mg/kg; subcutaneous L9LS at 5 mg/kg; intramuscular L9LS at 5 mg/kg; and CHMI controls who did not receive L9LS. The primary endpoint counted participants reporting local reactogenicity within seven days after L9LS administration. Its population included L9LS recipients with diary-card safety data (N=23).

The registry record reports zero serious adverse events and zero deaths in each group. It lists CHMI parasitemia and pharmacokinetic outcomes, but their results, the primary endpoint counts, and a detailed statistical analysis plan are not reported in the registry record.