Trial to Evaluate CIS43LS in Healthy Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial to Evaluate CIS43LS in Healthy Adults (NCT04206332), a non-randomized phase 1 study. The primary outcome is Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration.

2. Clinical Question

3. Trial Design

This is a completed Phase 1, dose-escalation, open-label trial with experimental controlled human malaria infections. The registry lists a non-randomized allocation, no masking, and a sequential study model. Enrollment was 71. The study began on 2020-01-07, and primary completion was recorded as 2022-02-28. The sponsor is the National Institute of Allergy and Infectious Diseases (NIAID).

The study enrolled healthy, malaria-naive adults and organized the regimens into Parts A, B, and C. CIS43LS was administered by intravenous infusion or subcutaneous injection at a range of doses. Some groups were intended to participate in CHMI, in which participants were bitten by mosquitoes carrying the malaria parasite in a controlled setting. The record describes control participants who did not receive CIS43LS, but this was not a randomized comparison. Group membership and challenge participation depended on the study part and regimen.

The design description includes changes in who participated in later parts. Part B, Group 7 included participants previously enrolled in Part A as well as newly enrolled Part B participants. Part B, Group 8 included people who received CIS43LS in Part A but did not receive it again in Part B; they were enrolled to complete CHMI. Group 5 did not undergo CHMI because of COVID-19-related restrictions. These details matter when interpreting group counts: the groups do not represent simple, independent treatment arms with identical histories.

Participants were monitored after administration and recorded symptoms on diary cards for 7 days. Follow-up included blood draws and checks for health changes or problems, with up to 12 follow-up visits described. The record lists pharmacokinetic outcomes, including maximum observed serum concentration, time to maximum concentration, beta half-life, and clearance rate. A detailed protocol, formal sample-size justification, and complete statistical analysis plan 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.

Before assignment: A subgroup of 10 participants from Part A who continued to Part B is counted twice: 4 Part A participants received a 2nd CIS43LS dose of 20 mg/kg IV in Part B (1 received 5 mg/kg IV, 1 received 5 mg/kg SC, and 2 received 20 mg/kg IV in Part A) and 6 did not receive CIS43LS in Part B: 3 enrolled as back up in the 20 mg/kg IV group (1 received 5 mg/kg IV, 1 received 5 mg/kg SC and 1 received 20 mg/kg IV in Part A) and 3 enrolled in CHMI (2 received 40 mg/kg IV and 1 enrolled in CHMI in Part A)

Only the first 6 of 17 groups are shown.

Part A

Reasons for not completing this period:

Part B

Reasons for not completing this period:

Part C

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Population included all enrolled participants who received CIS43LS and provided safety data (via diary card). A subgroup of 4 participants from Part A who continued to Part B are counted twice, and received a second CIS43LS dose intravenously (IV): 4 received CIS43LS at a dose of 20 mg/kg IV in Part B (1 had previously received 5 mg/kg IV, 1 had received 5 mg/kg subcutaneously, and 2 had received 20 mg/kg IV). No participants enrolled in Group 6: CIS43LS (5 mg/kg SC).

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: A total of 71 participants enrolled; however, 10 participants previously enrolled in Part A and who were later enrolled in Part B are counted twice (once in Part A and again in Part B).

Only the first 6 of 18 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 CIS43LS Product Administration, measured over 7 days after CIS43LS product administration, at approximately Week 1.

The primary endpoint is the number of participants reporting local reactogenicity signs and symptoms within 7 days of CIS43LS administration, with assessment at approximately Week 1. It is a participant-count endpoint: for each symptom, a participant was counted once at the worst severity reported during the period. The count for any local symptom represents participants reporting at least one local symptom, classified at the worst severity. Participants recorded solicited symptoms on a diary card, which clinic staff reviewed at a follow-up visit. Severity grading used the stated DAIDS table for grading adverse events.

This kind of endpoint is used to describe short-term local tolerability after administration. Counting each person once per symptom at the worst severity avoids treating repeated reports of the same symptom as separate participants, while retaining severity information. It is still a descriptive safety measure: counts alone do not establish that an event was caused by CIS43LS, and comparisons across small non-randomized groups may be affected by differences in participants, dose, route, study part, and prior exposure.

The registry record describes the endpoint and its population but does not report the endpoint’s participant counts by symptom or severity. It therefore does not permit a numerical account of local reactogenicity from the primary outcome. The serious and other adverse-event counts posted separately are safety information, but they are not substitutes for the missing primary endpoint results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial’s primary endpoint is a count of participants who experienced local symptoms, classified by symptom and worst severity during the 7 days after administration. Because the outcome is expressed as people with an event, the relevant raw information is a count of affected participants within a group. The denominator is the number of participants whose safety data were available for that endpoint. The registry record explains the endpoint population but does not post its symptom-specific counts or analysis results.

What a participant count describes

A participant count answers how many people in a defined group met an event definition. It is different from a count of all symptom reports: the endpoint counts each participant once for each symptom at the worst severity they reported. The any-local-symptom measure counts participants reporting any local symptom at the worst severity. This definition helps prevent repeated reports by one person from being treated as multiple people, but it does not make the groups comparable by itself. Differences in group size, dose, route, or study history remain important.

For binary outcomes, analysts often summarize the proportion of participants with an event and may compare that proportion between groups. Such a comparison needs a well-defined target contrast and suitable assumptions. In this trial, allocation was non-randomized, and the registry record itself cautions that the arms are not a like-for-like control comparison. Differences can reflect the regimens, but can also reflect who entered each group, when they entered, or what procedures they underwent. No adjusted or unadjusted comparative estimate is reported in the registry record.

Why uncertainty matters

General explanation: a confidence interval gives a range of estimates compatible with the observed data under a specified statistical model and its assumptions. With small groups, event counts can be imprecise, and a single participant can have a visible influence on a group’s summary. The interval’s width is therefore useful alongside the point estimate. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from that endpoint’s posted results.

General explanation: a p-value is a measure of how inconsistent observed data are with a specified null model, assuming the model and analysis conditions hold. It is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. The registry record reports no analyses, so no p-values or formal comparison results are available for interpretation.

Design and analysis assumptions

The sequential design and dose escalation mean that groups arose in stages rather than through random allocation. The routes included intravenous infusion and subcutaneous injection, while dose levels differed. Some participants were enrolled in more than one part; the primary endpoint population description says a subgroup of 4 continuing participants was counted twice. That feature means a participant-level count across all records cannot automatically be interpreted as a count of unique people. The record does not describe an analysis that adjusts for repeated participation.

General explanation: randomization can balance measured and unmeasured characteristics on average, while non-randomized group assignment may leave groups different before treatment. Masking can reduce some forms of expectation or assessment bias, but this trial had no masking. These design features do not invalidate descriptive safety counts, but they limit causal interpretation of comparisons among groups.

The registry lists pharmacokinetic outcomes such as maximum observed serum concentration, time to maximum observed concentration, beta half-life, and clearance rate. These outcomes describe how drug concentration changes over time and are distinct from the primary symptom-count endpoint. Detailed methods for their estimation, any transformations, handling of measurements below assay limits, and model specifications are not reported in the registry record.

Planning illustrations are not observed power

The study’s own sample-size justification is not reported in the registry record. Planning illustrations based on an observed effect are not the trial’s original design rationale and do not describe the probability that the completed trial detected an effect. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. For time-to-event outcomes, the illustration uses total events; other illustrations are expressed as participants per arm. These are hypothetical planning assumptions, not evidence of achieved power, and they do not repair the lack of randomization or missing endpoint results.

General explanation: over-dispersion matters when the variability in observed counts exceeds what a basic count model assumes. Ignoring it can make standard errors too small and confidence intervals too narrow. No dispersion value or count-model analysis is reported for this trial’s primary endpoint, and the endpoint is specified as a participant count rather than a repeated-event count. The record does not state that an over-dispersion adjustment was used.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 17 outcome measures, including the primary local-reactogenicity endpoint and pharmacokinetic outcomes for Parts A and B and for Part C. It reports zero analyses. No multiplicity strategy is reported in the registry record. That means the record does not say whether any adjustment, hierarchy, or other procedure was planned to account for examining multiple outcomes, symptoms, severities, doses, routes, or study parts. Without the statistical analysis plan, it is not possible to determine which comparisons were confirmatory and which, if any, were exploratory.

The registry describes diary-card collection and follow-up, but does not report the amount or pattern of missing primary endpoint data, whether diary cards were incomplete, or how missing observations were handled. The endpoint population is described as CIS43LS recipients who provided safety data via diary card. A result restricted to participants with safety data may differ from one based on all enrolled participants, but the registry record does not provide a missing-data analysis or enough outcome information to assess that possibility.

Analysis populations are not fully specified in the posted results. The record notes that a subgroup of 4 participants who continued from Part A to Part B was counted twice for the endpoint population description. It does not report how repeated participation, incomplete follow-up, or eligibility for CHMI was handled in statistical analyses. The listed enrollment of 71 is not necessarily the denominator for every safety or pharmacokinetic outcome.

These gaps limit interpretation of precision and robustness. No imputation method, sensitivity analysis, protocol-deviation handling, interim analysis plan, or prespecified primary comparison is reported in the registry record. They should be treated as unreported information, not assumed to have been absent from all study documentation.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: perirectal abscess (25.0%).

The registry’s adverse-event summaries list participants at risk, participants affected by serious events, participants affected by other events, and deaths for each group. Serious events were recorded as zero in every listed group except Part B, Group 9, which had one serious event among four participants at risk. The listed death count is zero in every group. The record names Perirectal Abscess as the top serious term and gives 25.0% for that term.

These entries are descriptive counts. They do not establish that CIS43LS caused an event, and the record does not provide a causal assessment for the serious event. The 25.0% figure should be read as the registry’s reported value for the named term, not as a general estimate of risk across all participants or regimens. The groups differ in size and study history, and one control group did not undergo CHMI. Comparisons between these entries are therefore not randomized treatment comparisons.

Zero recorded deaths or serious events in a group does not prove that the underlying risk is zero. Small groups provide limited information about uncommon events. The adverse-event summaries also do not replace the missing primary local-reactogenicity results: they address different safety categories and reporting definitions.

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

The posted record establishes that this was a completed, non-randomized, open-label Phase 1 study of CIS43LS in healthy, malaria-naive adults, with dose escalation and controlled human malaria infection procedures. It describes intravenous and subcutaneous administration, symptom monitoring after dosing, follow-up, and pharmacokinetic outcomes. It also records adverse-event counts by group, including one serious event in Part B, Group 9 and no deaths in the listed groups.

The record does not report the primary endpoint counts for local reactogenicity, statistical analyses, confidence intervals, or formal comparisons. It also does not report the CHMI efficacy outcomes. The posted material therefore cannot quantify the frequency or severity distribution of local symptoms by regimen, estimate comparative treatment effects, or determine how precisely any such effects were measured. A trial objective referring to protective efficacy is not itself evidence of an efficacy result.

The sequential non-randomized design, lack of masking, small group sizes, varied doses and routes, and differing participant histories are relevant when interpreting the adverse-event summaries. They limit the extent to which differences between groups can be attributed to the intervention. The control groups were included in the challenge setting but were not assigned through randomization; Part A, Group 5 did not undergo CHMI because of COVID-19-related restrictions.

General statistical explanation: absence of a reported comparison is not evidence that groups are equivalent, and an event count alone does not establish causation. The record also does not give enough information to assess the planned handling of missing data, multiplicity, or repeated participation. The responsible conclusion is limited to the design and counts that are posted; broader conclusions about safety or protection are not supported by the registry record alone.

13. Why This Trial Matters Statistically

This trial is statistically notable because its design combines sequential dose escalation, two administration routes, and controlled human malaria infection procedures, while allocation is non-randomized and masking is absent. Those features make the study useful for describing how the investigation was organized and what outcomes were monitored, but they also make comparisons across groups vulnerable to differences in participant composition and study history.

The primary endpoint is a participant-level safety count with a specified recall period and severity rule. Its definition illustrates why an endpoint needs to state what counts as an event, the time window, and how repeated symptoms are handled. Here, each participant was counted once per symptom at the worst severity reported during 7 days. Yet the registry record does not post the actual primary endpoint counts or analyses, leaving the central descriptive safety outcome unavailable for statistical interpretation.

Group histories also matter. Some participants continued across study parts and were counted twice in the described primary endpoint population, while a group intended for CHMI did not undergo the challenge because of COVID-19-related restrictions. These details illustrate why enrollment totals, endpoint denominators, unique participants, and challenge participants are not interchangeable concepts.

Finally, the posted adverse-event counts show why descriptive safety summaries should not be mistaken for causal comparisons. Small, non-randomized groups can identify events for reporting, but do not by themselves establish comparative risk. With no analyses reported, the distinction between collected outcomes and interpretable estimates is especially important.

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 registry record provides limited outcome detail for statistical assessment. It defines the primary local-reactogenicity endpoint but does not report its counts by symptom or severity, or any analysis results. The record lists zero analyses and does not include confidence intervals or formal comparisons. Protective efficacy outcomes from CHMI are not reported in the posted results.

Allocation was non-randomized and masking was absent. Groups differed by dose, route, study part, and challenge participation. The record specifically notes that the arms are not a like-for-like control comparison. Part A, Group 5 did not undergo CHMI because of COVID-19-related restrictions, and Part B included participants with prior CIS43LS exposure. These features constrain direct comparisons.

Enrollment was 71, but the endpoint population description says a subgroup of 4 participants continuing from Part A to Part B was counted twice. The record does not provide a full participant flow for each endpoint, or explain in detail how repeated participation was handled in analysis. Missing diary data, missing follow-up, and missing pharmacokinetic measurements are not quantified. Methods for missing data, multiplicity, interim analyses, and statistical adjustment are not reported in the registry record.

Group sizes in the adverse-event summaries are small, and the counts are descriptive. The posted information does not establish whether events were considered related to CIS43LS. The record also does not report the study’s sample-size justification or a complete statistical analysis plan. These limitations mean that the available counts should not be generalized beyond the specific groups and reporting definitions recorded.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Trial to Evaluate CIS43LS in Healthy Adults — NCT04206332.
• Registry record last updated 2023-04-18; status last verified 2023-04.
• Results first posted 2023-04-18.
• 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

NCT04206332 is a completed Phase 1, non-randomized, open-label, sequential dose-escalation trial of CIS43LS in healthy adults who had never been infected with malaria. Enrollment was 71; the recorded study start was 2020-01-07 and primary completion was 2022-02-28. CIS43LS was administered intravenously or subcutaneously at multiple dose levels. The study included controlled human malaria infection challenges and control groups, with one intended challenge group not undergoing CHMI because of COVID-19-related restrictions.

The primary endpoint counts participants reporting local reactogenicity symptoms within 7 days after administration, but primary endpoint results and statistical analyses are not reported in the registry record. The adverse-event summaries record one serious event in Part B, Group 9, zero deaths in the listed groups, and Perirectal Abscess as the top serious term at 25.0%. The record does not report comparative efficacy results, a full statistical analysis plan, or the trial’s sample-size justification.