Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria. (NCT03334747), a randomized phase 2 study. The primary outcome is Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST).

2. Clinical Question

The study was designed to evaluate safety as KAE609 doses increased, rather than to establish a definitive comparative treatment effect. The registry description says that recruitment could be suspended if specified numbers of participants in a cohort reached the liver-enzyme threshold, followed by a safety review committee assessment. Further study progression depended on that committee's decision. The record does not report whether a suspension or such a review occurred.

3. Trial Design

NCT03334747 was a completed Phase 2, randomized, open-label, parallel-group, dose-escalation study sponsored by Novartis Pharmaceuticals. The registry lists enrollment of 188. The study started on 2017-11-16, and primary completion was 2019-11-23. Participants were adults with uncomplicated Plasmodium falciparum malaria.

The KAE609 regimens varied by dose and duration: single doses of 10 mg, 25 mg, 50 mg, 75 mg, and 150 mg, and once-daily doses for 3 days at 10 mg, 25 mg, and 50 mg. The ninth listed arm was Coartem control. The registry describes the dose cohorts as sequential and increasing, while also identifying the study allocation as randomized. It does not report the randomization sequence, allocation concealment, or the number randomized to each arm as a design detail.

There was no masking. This matters when interpreting outcomes that may depend on clinical assessment or decisions, although the primary endpoint is based on laboratory measures of ALT and AST. The registry does not report whether laboratory assessment was blinded to treatment assignment.

The primary endpoint was assessed through Day 29, and the description frames the evaluation as covering a 4 weeks study period. The safety analysis population included participants with baseline and at least one post-baseline ALT or AST assessment. Arm denominators for the primary endpoint vary, and the registry does not explain each difference between those analysis denominators and the enrollment figure.

The record also lists clinical, parasitological, and pharmacokinetic secondary outcomes, including response measures, parasite and fever clearance times, recurrence outcomes, and concentration measures. It does not report a formal sample-size justification or a full statistical analysis 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.

Before assignment: Approximately, 210 patients were planned to be randomized in six cohorts (KAE609: 150 and Coartem: 60). A total of 188 (KAE609: 137 and Coartem: 51) subjects were randomized in five cohorts. Cohort 6 was optional and never initiated. Two of the 188 randomized subjects were not treated and therefore were excluded from all analyses.

Only the first 6 of 9 groups are shown.

Treatment Phase

Reasons for not completing this period:

Follow-Up Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Set (SAF). Only participants with baseline and at least one post-baseline assessment for either ALT or AST are included in the analysis.

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: Randomized set (RAN)

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST), measured over Day 29.

The primary endpoint is the percentage of participants with at least a 2 CTCAE grades increase from baseline in ALT or AST by Day 29. ALT and AST are liver enzymes measured in blood; a rise in their toxicity grade can indicate a change in liver-related laboratory status. The endpoint combines either enzyme meeting the stated grade-increase threshold, so it is a participant-level safety measure rather than a measure of the average enzyme concentration.

The endpoint is relevant to this dose-escalation study because the stated purpose was to characterize hepatic safety across single and multiple ascending doses of KAE609. The registry description also specifies cohort thresholds that could trigger suspended recruitment and a safety review. This makes the measure part of a safety-monitoring question, not simply a general comparison of average laboratory values.

The primary population is the Safety Set, defined as participants with baseline and at least one post-baseline assessment for either ALT or AST. This definition allows an assessment when follow-up measurements exist, but it also means the endpoint denominator may not include every enrolled participant. The registry record does not describe how missing assessments were handled beyond that population definition, or whether the grade increase had to be confirmed.

The endpoint does not by itself summarize all hepatic events, establish why a laboratory change occurred, or capture every aspect of clinical safety. Its interpretation depends on the threshold, observation period, analysis population, and completeness of follow-up. Details such as the CTCAE version and any adjudication process are not reported in the registry record.

7. Results Posted in the Registry

• KAE609 10 mg QD 3 Days: 0.0% (0/10) versus 3.9% (2/51) on control; risk difference -3.9 percentage points (95% CI -9.2 to 1.4); unadjusted two-proportion z-test p = 0.524.
• KAE609 25 mg SD: 0.0% (0/12) versus 3.9% (2/51) on control; risk difference -3.9 percentage points (95% CI -9.2 to 1.4); unadjusted two-proportion z-test p = 0.486.
• KAE609 25 mg QD 3 Days: 0.0% (0/20) versus 3.9% (2/51) on control; risk difference -3.9 percentage points (95% CI -9.2 to 1.4); unadjusted two-proportion z-test p = 0.369.
• KAE609 50 mg SD: 0.0% (0/21) versus 3.9% (2/51) on control; risk difference -3.9 percentage points (95% CI -9.2 to 1.4); unadjusted two-proportion z-test p = 0.357.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Parasite Clearance Time (PCT)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • KAE609 10 mg SD: mean 26.80 versus 36.20 on control; difference -9.40 (95% CI -22.32 to 3.52), standardized effect d = -0.37; z-test p = 0.154.
  • KAE609 10 mg QD 3 Days: mean 27.70 versus 36.20 on control; difference -8.50 (95% CI -20.65 to 3.65), standardized effect d = -0.34; z-test p = 0.170.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between KAE609 10 mg SD and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between KAE609 10 mg QD 3 Days and the control. The interval gives the range of effects that remain compatible with the data.

Fever Clearance Time (FCT)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • KAE609 10 mg QD 3 Days: mean 2.00 versus 13.00 on control; difference -11.00 (95% CI -19.41 to -2.59), standardized effect d = -0.39; z-test p = 0.010.
  • KAE609 25 mg QD 3 Days: mean 22.00 versus 13.00 on control; difference 9.00 (95% CI -19.76 to 37.76), standardized effect d = 0.21; z-test p = 0.540.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for KAE609 10 mg QD 3 Days than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between KAE609 25 mg QD 3 Days and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists a broad set of secondary outcomes, including PCR-corrected and uncorrected response measures, parasite and fever clearance times, recurrence outcomes, and pharmacokinetic measures. Numerical summaries are available for parasite clearance time and fever clearance time. These outcomes address different dimensions of the study: parasite and fever resolution are clinical or parasitological measures, whereas concentration and exposure measures describe drug disposition. They are not substitutes for the primary liver-enzyme safety endpoint.

Across the secondary findings that have numerical summaries, estimates vary by dose and outcome, and their precision is uneven. Some means are accompanied by standard errors, while other arm summaries lack a reported dispersion value. One fever-clearance mean is absent. The registry does not report inferential analyses for these secondary outcomes beyond the unadjusted recalculations, and it does not report numerical results for every secondary outcome named in the record. The overall pattern should therefore be treated as exploratory and incomplete rather than as a unified efficacy or safety conclusion.

The primary endpoint concerns a defined hepatic laboratory threshold, while the secondary outcomes concern response, timing, recurrence, and pharmacokinetics. A pattern in one domain does not establish a pattern in another. In particular, secondary outcome results cannot resolve the broad uncertainty around the primary endpoint estimates.

Unadjusted secondary analyses carry less weight because the study includes multiple outcomes and dose comparisons, and the registry does not report a multiplicity adjustment or a prespecified hierarchy for interpreting them. When many unadjusted tests are considered, chance findings become more plausible. The record also does not provide enough detail about missing secondary outcome data or analysis populations to determine how comparable the estimates are across outcomes.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29
• Parasite Clearance Time (PCT)
• Fever Clearance Time (FCT)
• Time to Recrudescence and Reinfection at Study Day 29
• Maximum Peak Observed Concentration (Cmax)
• Tmax
• AUC0-24
• Half-life (T^1/2)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: the participant either met the stated ALT-or-AST grade-increase threshold during the assessment period or did not. The registry reports each arm's percentage and a 95% confidence interval. It also lists Fisher Exact p-values for KAE609 arms, but does not state the precise hypothesis tested by those reported analyses. Separate unadjusted recalculations compare eligible KAE609 arms with pooled Coartem control.

What does a confidence interval express?

In general, a confidence interval describes the uncertainty around an estimate under the method used to calculate it. For a percentage based on a relatively small analysis group, a small change in the number of observed events can materially affect the estimated percentage. Intervals can therefore be broad even when the displayed point estimate is zero or close to zero. The interval is not a range containing a fixed proportion of individual outcomes; it concerns uncertainty in the estimated group-level value.

The registry gives 95% confidence intervals for the primary percentages, but the method used to construct them is not reported in the registry record. That omission makes it difficult to assess whether the intervals used a particular small-sample procedure or how the procedure handles zero-event groups. The intervals are still useful for showing that the estimates are not highly precise.

How should the unadjusted comparisons be read?

The recalculated contrasts compare each KAE609 arm with the pooled Coartem control using unadjusted summary information. The reported metric is a risk difference: conceptually, it expresses the difference between the event proportions in the compared groups. A confidence interval spanning zero is compatible with no difference as well as with differences in either direction, within the range of values covered by the interval. The posted unadjusted p-values do not account for the many comparisons and outcomes considered.

These recalculations are not adjusted for covariates, sequential cohort structure, or multiple testing. The registry does not report a model that accounts for those features. They should be treated as simple descriptive comparisons and not as replacements for a prespecified sponsor analysis.

Why does sparse event information matter?

General statistical reasoning: when an outcome is uncommon and group sizes are limited, estimates can be unstable. Some groups have no recorded events, while others have a small number. Under those conditions, standard large-sample approximations may not represent the uncertainty well. Exact methods such as Fisher's Exact test are often used for sparse categorical data, but the record does not state enough about the sponsor's hypotheses or implementation to interpret its listed p-values as direct tests against control.

Zero events in a group should not be interpreted as proof of no risk. The upper confidence limits show that nonzero event percentages remain compatible with the observations. Likewise, a point estimate above the control percentage does not establish a higher underlying risk when the uncertainty is substantial.

What do the planning illustrations mean?

The planning illustrations use the observed effect as a starting point and show participant requirements under stated assumptions, including a two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation. Rows describe planning for 100%, 75%, and 50% of the observed effect. These are hypothetical design illustrations, not the trial's original sample-size justification and not observed power. The registry does not report the study's own sample-size rationale.

For a binary outcome with a small observed event frequency, planning directly from the observed effect can produce very large requirements and can be sensitive to the chosen effect fraction. The illustrative values should not be treated as evidence that the completed study was adequately powered for a comparative safety conclusion. The study's stated objective was safety characterization during dose escalation; a formal comparative power target is not reported.

Other statistical details are also absent. The record does not report an interim-analysis plan, a multiplicity strategy, covariate adjustment, a missing-data imputation method, or sensitivity analyses for the primary outcome. These omissions limit reconstruction of the full inferential framework from the registry record.

11. Confidence Intervals and Precision

The primary percentages are accompanied by 95% confidence intervals, which communicate uncertainty in the arm-level estimates. The intervals are broad relative to many of the point estimates. For KAE609 10 mg SD, the estimate is 11.1% with an interval from 0.3% to 48.2%. For KAE609 150 mg SD, the estimate is 4.5% with an interval from 0.1% to 22.8%. The control estimate is 3.9%, with an interval from 0.5% to 13.5%.

For groups with 0.0% observed events, the lower confidence limit is 0.0%, but the upper limits remain substantial: 30.8% for KAE609 10 mg QD 3 Days, 26.5% for KAE609 25 mg SD, 16.8% for KAE609 25 mg QD 3 Days, 16.1% for KAE609 50 mg SD, 17.6% for KAE609 50 mg QD 3 Days, and 16.1% for KAE609 75 mg SD. These ranges show why absence of observed events is not equivalent to precise evidence that the event cannot occur.

The comparison intervals also convey uncertainty. For KAE609 150 mg SD versus pooled control, the recalculated risk-difference interval runs from -0.096 to 0.108. For the other reported contrasts, the recalculated interval also spans no difference. Such intervals are compatible with differences in either direction, and do not establish equivalence.

Precision is constrained by the arm-level denominators, which range from 9.0 to 51.0 for the primary outcome. The record does not report the method used for the percentage confidence intervals, so their construction cannot be independently assessed from the registry entry alone. The posted estimates are best understood as imprecise safety descriptions rather than finely resolved comparisons.

12. Analyses Reported by the Sponsor

The registry lists Fisher Exact analyses for the KAE609 arms, with p-values of 0.391 for KAE609 10 mg SD and 1 for each of KAE609 10 mg QD 3 Days, KAE609 25 mg SD, KAE609 25 mg QD 3 Days, KAE609 50 mg SD, KAE609 50 mg QD 3 Days, KAE609 75 mg SD, and KAE609 150 mg SD. The record does not specify the null hypothesis or comparison underlying these arm-specific p-values. They therefore should not be assumed to be tests of each KAE609 regimen against pooled Coartem control.

The unadjusted recalculations use the posted group summaries to compare KAE609 arms with pooled control. Those comparisons have confidence intervals that include no difference and unadjusted p-values that do not indicate a clear contrast. They are not the same analysis as the Fisher Exact results listed in the registry, and they do not replace the sponsor's analysis. The discrepancy flag is false, so there is no identified conflict requiring the sponsor's analysis to take precedence over a differing recalculation.

Because the reported test hypotheses are not described and the recalculations are unadjusted, neither set of p-values should carry more weight than the underlying event percentages and their uncertainty. A complete statistical analysis plan is not reported in the registry record.

13. Multiplicity, Missing Data and Analysis Populations

The registry presents a primary safety endpoint across multiple KAE609 regimens and pooled control, alongside several secondary outcomes. This creates a multiplicity issue: repeated testing across arms and outcomes can increase the chance of at least one nominally notable result arising by chance. The registry record does not report a multiplicity adjustment, a testing hierarchy, or which secondary outcomes were intended to be confirmatory. The recalculated comparisons are explicitly unadjusted, so their p-values should be interpreted cautiously.

The primary analysis population is defined as the Safety Set, including only participants with baseline and at least one post-baseline assessment for either ALT or AST. This is a stated analysis-population rule, but it does not explain how participants without qualifying measurements were handled or whether any additional missing-data rules were applied. The registry does not report imputation, sensitivity analyses, or reasons for missing assessments. It also does not explain the variation in primary analysis denominators by arm.

For secondary outcomes, the available record is less complete: some summaries lack dispersion information, one fever-clearance mean is absent, and the numerical results for all listed outcomes are not reported. Analysis populations and missing-data procedures for those outcomes are not reported in the registry record.

The protocol description includes cohort thresholds for suspending recruitment and initiating review of liver safety and other relevant data. However, interim analyses, the timing and conduct of any safety reviews, and the committee's decisions are not reported. The registry also does not describe a formal statistical analysis plan or sample-size justification. These gaps limit assessment of whether the analyses followed prespecified rules and how missing observations, multiplicity, and sequential dose escalation were handled.

14. 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: blood bilirubin increased (5.3%), thrombocytopenia (4.8%), blood alkaline phosphatase increased (4.8%), alanine aminotransferase increased (4.5%).

The adverse-event record reports serious adverse events separately from other adverse events. Serious events were recorded in 0 among 10 participants in KAE609 10mg SD, 0 among 10 in KAE609 10mg QD@3 Days, 0 among 12 in KAE609 25mg SD, 0 among 20 in KAE609 25mg QD@3 Days, and 0 among 21 in KAE609 50mg SD. The corresponding serious-event counts were 1 among 19 in KAE609 50mg QD@3 Days, 2 among 21 in KAE609 75mg SD, 1 among 22 in KAE609 150mg SD, and 1 among 51 in pooled Coartem. Deaths were recorded as 0 in every listed group.

These counts describe what was recorded during the study; they do not establish comparative risk. Serious events are uncommon in these groups, so the estimates are uncertain, and the record does not provide confidence intervals or adjusted comparisons for these figures. The other adverse-event counts are also reported, but they are not equivalent to the primary ALT-or-AST grade-increase endpoint.

The listed serious-event terms and percentages include Blood bilirubin increased at 5.3%, Thrombocytopenia at 4.8%, Blood alkaline phosphatase increased at 4.8%, and Alanine aminotransferase increased at 4.5%. The registry record does not provide further context about event timing, relatedness, or severity grading for those terms. These summaries should be read alongside, not substituted for, the defined primary endpoint.

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

The primary results establish that the registry recorded a low percentage of participants meeting the specified ALT-or-AST grade-increase threshold in most arms, with higher displayed percentages in KAE609 10 mg SD and KAE609 150 mg SD than in the other KAE609 groups. The pooled Coartem percentage was 3.9%. The confidence intervals are broad, including for groups with no observed events, and the recalculated comparisons do not demonstrate a clear difference from pooled control.

These findings do not show that hepatic risk is absent. A zero observed percentage is compatible with a nonzero underlying event frequency, as reflected by the upper confidence limits. Nor do the findings show that KAE609 and Coartem have equivalent safety: equivalence requires a specified margin and a suitable design and analysis, neither of which is reported in the registry record.

The findings also do not establish that any observed laboratory change was caused by KAE609. The study description frames the endpoint as a safety assessment, but the available registry summaries do not include a causal analysis or detailed attribution information. The open-label design and dose-escalation structure are relevant context, while the record does not report the full procedures used to limit bias or account for cohort sequence.

More broadly, the endpoint captures one defined liver-enzyme threshold over the stated observation period. It does not represent every possible hepatic effect or the full benefit-risk profile of a treatment. Secondary measures address other questions and do not eliminate uncertainty in the primary safety estimates. The appropriate statistical conclusion is therefore descriptive: the posted data give observed event percentages with substantial uncertainty, not a definitive demonstration for or against a treatment effect.

16. Why This Trial Matters Statistically

This trial illustrates a common statistical challenge in early dose-escalation safety studies: the main purpose is to monitor and describe potential harms across dose cohorts, while the resulting group sizes may be too limited for precise comparisons. Here, the primary endpoint is clinically focused and defined by a laboratory grade threshold, but the arm-level estimates remain uncertain. Sparse outcomes make a zero count particularly easy to overinterpret unless the confidence interval is considered.

The design also combines randomized allocation with sequential, increasing-dose cohorts. Randomization is an important design feature, but the registry record does not explain allocation details or how the sequence of cohorts entered the study. For interpretation, it is important not to equate a randomized label with a fully powered comparative trial. The stated focus is hepatic safety and dose escalation, and a formal comparative sample-size rationale is not reported.

The registry's cohort suspension rules show how statistical thresholds can inform safety oversight. Such rules are not the same as a final statistical comparison: they trigger review, and the record says further progression depended on a safety review committee decision. The committee's actions are not reported, so the operational consequences of the rules cannot be reconstructed.

Finally, the results demonstrate why estimates, uncertainty intervals, and analysis definitions need to be read together. The Safety Set definition, changing denominators, missing-data uncertainty, multiple outcomes, and lack of reported multiplicity procedures all affect how much confidence can be placed in apparent between-group patterns. These are central features of interpreting registry results, not merely technical details.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary endpoint denominators differ by arm, and the registry does not explain all reasons for those differences. The Safety Set requires a baseline and at least one post-baseline assessment for ALT or AST; the record does not describe missing-data handling beyond that inclusion rule. Consequently, the posted percentages may not represent every enrolled participant.

The study was open-label and used a dose-escalation design with sequential cohorts. Although allocation is listed as randomized, the record does not give the randomization procedure, concealment details, or timing of cohort enrollment. It does not report whether laboratory assessors were blinded. These details matter when assessing potential bias and comparability across groups.

The primary event is infrequent in the posted groups, and confidence intervals are wide. The record does not specify the method for constructing those intervals or provide adjusted effect estimates. The reported Fisher Exact p-values do not have a clearly stated comparison in the registry record, while the direct recalculations are unadjusted and not corrected for multiple comparisons.

The registry describes safety review thresholds but does not report whether they were reached, what reviews occurred, or what decisions followed. It also does not report an interim-analysis plan, the full statistical analysis plan, a formal sample-size justification, or a prespecified multiplicity strategy. Numerical information for secondary outcomes is incomplete, and some secondary summaries lack dispersion estimates.

These limitations constrain interpretation to the posted descriptive results and simple unadjusted recalculations. They do not invalidate the recorded observations, but they prevent a precise or comprehensive assessment of comparative hepatic safety from the registry record alone.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria. — NCT03334747.
• Registry record last updated 2021-10-11; status last verified 2021-10.
• Results first posted 2020-09-25.
• 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.

21. Record Summary

NCT03334747 was a completed Phase 2, randomized, open-label, parallel dose-escalation study of KAE609 in adults with uncomplicated Plasmodium falciparum malaria. The registry lists enrollment of 188 and pooled Coartem control. The primary endpoint was the percentage of participants with at least a 2 CTCAE grades increase from baseline in ALT or AST by Day 29.

Primary event percentages ranged from 0.0% to 11.1% across the KAE609 arms; pooled Coartem control was 3.9%. The 95% confidence intervals were broad. Unadjusted recalculated comparisons with control did not show a clear difference, but they are not confirmatory analyses. The registry does not report a full statistical analysis plan, multiplicity strategy, or detailed missing-data procedures. The posted results are best read as imprecise safety descriptions rather than definitive comparative conclusions.