Fexinidazole in Human African Trypanosomiasis Due to T. b. Rhodesiense: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fexinidazole in Human African Trypanosomiasis Due to T. b. Rhodesiense (NCT03974178), a non-randomized phase 2, phase 3 study. The primary outcome is Percentage of Evaluable Patients With Stage 2 r-HAT Who Died by the End of Hospitalization, Considering Only Deaths Possibly Related to r-HAT or Fexinidazole.

2. Clinical Question

The trial asks whether a ten-day course of oral fexinidazole can be used for human African trypanosomiasis caused by Trypanosoma brucei rhodesiense, a disease described in the record as r-HAT. The study includes patients classified as having stage 1 or stage 2 disease. The registry describes stage 1 patients as having no trypanosomes in cerebrospinal fluid, but trypanosomes in blood and/or lymph and cerebrospinal fluid white blood cells at or below 5 cells/µL. Stage 2 includes trypanosomes in cerebrospinal fluid and/or blood or lymph, and/or cerebrospinal fluid white blood cells >5 cells/µL.

The record frames the clinical questions around the existing treatments: melarsoprol for stage 2 and suramin for stage 1. It asks whether short-term fatality and failure rates with fexinidazole are lower than those with melarsoprol for stage 2 disease, whether long-term failure is lower for that group, and whether fexinidazole can replace suramin for stage 1 disease. It also asks about safety across disease stages. These are stated aims, not conclusions established by the design or the results included in the registry record.

3. Trial Design

This is a multicentre, open-label clinical trial listed as phase 2 and phase 3. Its allocation is non-randomized, masking is absent, and the model is parallel. The registry lists 45 participants enrolled and the study status as completed. The listed start date is 2019-09-29, and primary completion is dated 2021-11-30.

All participants received fexinidazole; the record describes oral treatment for 10 days in both stage groups. The stage 1 and stage 2 groups therefore represent disease-stage populations receiving the same intervention, not randomized treatment arms. The record does not list a concurrent melarsoprol or suramin group. Although the study aims compare fexinidazole outcomes with those existing treatments, a non-randomized, single-intervention design cannot by itself provide a like-for-like randomized comparison. The registry specifically cautions that the arms are not a like-for-like control comparison.

The planned follow-up included regular blood draws and lumbar punctures over 12 months to assess cure, alongside adverse-event recording, disease signs and symptoms, laboratory tests, vital signs, and electrocardiograms. The primary endpoint is narrower than the overall study aims: it concerns possibly related deaths among evaluable stage 2 patients by the end-of-hospitalization visit, described as Day 12-18. Other listed outcomes address treatment failure at the end of hospitalization and at 12 months, deaths across disease stages, and adverse events.

The registry record does not report the detailed protocol, a sample-size justification, or a randomized comparison. It also does not report a numerical primary-endpoint estimate or its confidence interval in the registry record for this analysis. Completion status means the study is recorded as completed; it does not, on its own, establish an endpoint result or resolve the stated comparisons with existing treatments.

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: The pre-treatment period of up to 7 days included screening and treatment of concurrent malaria and soil-transmitted helminthiasis. At the end of this period, all participants were treated with fexinidazole, regardless of the stage of human African trypanosomiasis due to Trypanosoma brucei rhodesiense (r-HAT) and treatment setting.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis is performed in evaluable patients with stage 2 r-HAT. A total of 35 patients with stage 2 r-HAT were enrolled and treated. One patient died during hospitalization, but the death was considered unrelated to r-HAT and/or the study treatment, as evaluated by the Investigator and the DSMB and accepted by the Sponsor. As per protocol, this patient was considered non-evaluable for efficacy purposes. There were 34 patients with stage 2 r-HAT who were evaluable.

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: All patients who took at least one dose of fexinidazole

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Evaluable Patients With Stage 2 r-HAT Who Died by the End of Hospitalization, Considering Only Deaths Possibly Related to r-HAT or Fexinidazole, measured over 12 to 18 days after start of treatment.

The primary endpoint is the percentage of evaluable patients with stage 2 r-HAT who died by the end of hospitalization, counting only deaths considered possibly related to r-HAT or fexinidazole. The time window is described as 12 to 18 days after treatment began, ending at the Day 12-18 End-of-Hospitalization Visit. The endpoint description says relatedness was assessed by the Data Safety Monitoring Board. It also notes that the WHO verbal autopsy questionnaire was used because anatomopathological techniques were not available at the study sites, except when death occurred in hospital and the investigator was present.

This endpoint focuses on early fatality in the stage 2 group, one of the study’s stated areas of concern. It is a binary outcome: each evaluable participant either meets the endpoint definition or does not. As a general statistical point, reporting a percentage alongside a confidence interval helps readers distinguish the observed event proportion from the uncertainty around that estimate. The endpoint’s listed dispersion measure is a 90% confidence interval, but numerical endpoint and interval results are not reported in the registry record.

The endpoint definition also affects who contributes to the analysis. A hospitalization death judged unrelated to both r-HAT and study treatment is classified as non-evaluable for efficacy purposes. A patient who leaves before the planned visit without medical discharge, with no outcome retrievable, is also described as non-evaluable. The registry narrative reports that one stage 2 patient died during hospitalization, but that death was considered unrelated to r-HAT and/or treatment by the Investigator and DSMB. That narrative does not give the numerical primary-endpoint result for the evaluable population.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary event summarized as a percentage of participants. A participant is counted as having the event only if death occurs within the specified hospitalization window and is considered possibly related to r-HAT or fexinidazole. The endpoint description assigns the relatedness assessment to the Data Safety Monitoring Board and specifies use of a verbal autopsy questionnaire when anatomopathological methods were unavailable. This definition is clinically focused, but it also means that classification of cause and relatedness is part of the endpoint measurement.

What does a confidence interval add?

In general, a confidence interval communicates uncertainty around an estimated quantity. For an event percentage, the interval reflects that the observed proportion is based on a finite group of participants and may differ from the underlying event rate in a broader population. A narrower interval generally indicates greater precision under the method’s assumptions; a wider interval indicates more uncertainty. The primary endpoint lists a 90% confidence interval, but its numerical limits are not reported in the registry record. Without those limits or the endpoint estimate, the precision of the primary result cannot be evaluated.

Confidence intervals do not correct for bias, replace a comparison group, or prove that an intervention caused an outcome. Their interpretation depends on the analysis population and endpoint definition. Here, the endpoint is restricted to evaluable stage 2 patients, and unrelated in-hospital deaths are treated as non-evaluable for efficacy. Patients who leave before the planned visit without medical discharge and for whom no outcome can be retrieved are also described as non-evaluable. These rules affect which participants enter the primary analysis and should be considered alongside any estimate.

Why does the analysis population matter?

An analysis population defines who contributes data to a particular result. The primary outcome description specifies evaluable patients with stage 2 r-HAT, rather than all enrolled participants. This is distinct from the overall enrollment figure and from safety summaries that may use participants at risk for adverse events. Different analysis populations can yield different denominators and address different questions. The registry record does not report a full account of analysis populations across the listed outcomes, nor does it report how missing outcome data were handled beyond the endpoint’s stated non-evaluable rules.

In general, excluding participants from an efficacy analysis can be consequential if the reasons for exclusion are related to prognosis or treatment response. The endpoint rules identify some circumstances that lead to non-evaluability, but the registry record does not report enough information to assess the extent or consequences of those exclusions. It also does not report a detailed missing-data plan or sensitivity analyses. These details are important because they help readers understand whether the analysis depends on assumptions about outcomes that were not observed.

What can the design say about treatment effects?

The trial is non-randomized, open-label, and lists fexinidazole as the intervention. Randomization, in general, helps balance measured and unmeasured prognostic factors between treatment groups. This trial record does not describe a randomized control group. As a result, any comparisons with melarsoprol or suramin would require information beyond a direct concurrent randomized contrast; the registry record does not report such a comparison analysis. Differences between outcomes in this study and outcomes from another setting could reflect differences in patients, care, follow-up, or outcome assessment as well as treatment.

Open-label means the record lists no masking. In general, knowledge of treatment can influence reporting, clinical management, or assessment, although the extent depends on the outcome and procedures. Death is less open to subjective interpretation than some outcomes, but attribution of cause or relatedness can still involve judgment. The record describes a DSMB assessment and the use of verbal autopsy in some circumstances; it does not report further detail about adjudication procedures.

How should planning calculations be read?

General sample-size planning uses assumptions about an effect to estimate how much information a future comparison might need. The planning illustration associated with this record is described as based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is not described as the trial’s own design calculation. Any resulting sample-size values are planning illustrations, not observed power, and should not be mistaken for evidence that the completed trial had a particular probability of finding an effect. The registry record does not report the original sample-size justification.

These planning assumptions also differ from the listed clinical trial design: the study is non-randomized and does not list a concurrent comparator arm. Therefore, the equal-allocation two-arm calculation is a hypothetical planning framework, not a description of how participants were assigned in this trial. The record does not report the rationale for the planning effect or whether the trial was designed around a particular primary endpoint threshold.

What is multiplicity?

Multiplicity arises when a study evaluates several outcomes or makes several statistical comparisons. In general, testing many questions can increase the chance of at least one apparently notable result arising by chance if each is assessed without adjustment. This record lists 11 outcome measures and 6 analyses. The registry record does not report whether multiplicity adjustments were planned or applied, how outcomes were prioritized beyond the named primary endpoint, or how the analyses map to the outcome list. No conclusion about adjustment can therefore be drawn from the record alone.

Finally, the listed outcomes include treatment failure at different follow-up times, deaths, and adverse events. These outcomes capture different aspects of the study and should not be combined into a single conclusion. Their definitions, denominators, follow-up completeness, and analysis methods matter. The registry record does not report numerical primary or treatment-failure results in the available information, so those outcome estimates and their statistical uncertainty cannot be interpreted.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Patients With Stage 2 r-HAT")
n      <- c(34)
events <- c(0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Patients With Stage 2 r-HAT  34  0  0.0  0.0  10.3  0.0  10.2  0.1  10.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures and 6 analyses, including stage-specific treatment failure at the end of hospitalization and at 12 months, deaths, and adverse events. The primary endpoint is identified as possibly related death among evaluable stage 2 patients by the end-of-hospitalization visit. The registry record does not report whether statistical adjustments for multiple outcomes or analyses were planned or used. In general, when many outcomes are examined, unadjusted results may be more likely to include a chance finding; whether that concern applies to a particular conclusion depends on the analysis plan and the role assigned to each outcome.

Missingness and evaluability are especially relevant to the primary endpoint. The endpoint description classifies a death judged unrelated to r-HAT and study treatment as non-evaluable for efficacy purposes. It also classifies a patient who leaves before the planned visit without medical discharge, with no outcome retrievable, as non-evaluable. These are stated rules, but the registry record does not report the number of patients excluded under each rule, a complete flow of participants into each analysis, or sensitivity analyses examining alternative assumptions for missing outcomes.

The primary population is evaluable stage 2 patients; it is not simply all participants enrolled. Safety summaries list participants at risk by stage, while efficacy outcomes can use different eligibility and evaluability criteria. The registry record does not report a comprehensive description of all analysis populations or whether every listed outcome used the same denominator. These distinctions matter when comparing percentages across outcomes or time points.

In general, analysis choices for missing data and multiplicity should be interpreted in light of a prespecified statistical plan. The registry record does not report the detailed statistical analysis plan, the missing-data strategy, or the treatment of multiple comparisons. It is therefore not possible to determine from this record whether these issues were addressed in the analyses.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute kidney injury (2.9%), pneumonia (2.9%), urinary tract infection (2.9%).

The adverse-event listings separate stage 1 and stage 2 patients and give numbers at risk and numbers affected. In the serious-event category, the listing reports 0 affected among 10 stage 1 patients and 3 among 35 stage 2 patients. In the other adverse-event category, it reports 6 among 10 stage 1 patients and 16 among 35 stage 2 patients. These are counts from the registry listing; they should not be read as a comparison of treatment effects because both groups received fexinidazole and differ by disease stage.

The serious-event terms listed most prominently are acute kidney injury, pneumonia, and urinary tract infection, each reported as 2.9%. The record does not provide further details in the available information about timing, severity gradation, duration, or whether the listed terms refer to distinct participants. A participant can experience more than one event, so event terms should not automatically be added together to infer a number of affected people.

The registry also lists 1 death in the stage 2 group. The primary endpoint narrative says that the death during hospitalization was considered unrelated to r-HAT and/or study treatment by the Investigator and DSMB. Adverse-event counts and the primary efficacy endpoint use different definitions, so the death count should not be treated as the primary endpoint result.

These figures describe events recorded in this study; they do not establish comparative safety relative to another treatment. The registry record does not report a concurrent control group or detailed comparative safety analysis.

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

The record establishes that a completed, non-randomized, open-label trial evaluated oral fexinidazole in patients with stage 1 or stage 2 r-HAT. It states that the treatment course was 10 days and that participants were followed with assessments intended to monitor cure, adverse events, symptoms, laboratory findings, vital signs, and electrocardiograms. It also identifies a primary question focused on possibly related deaths among evaluable stage 2 patients during hospitalization.

The registry information does not report the numerical primary endpoint estimate or its 90% confidence interval. It also does not report numerical treatment-failure results for the listed time points. Therefore, the available record does not allow readers to quantify those outcomes or judge their precision. The narrative of one stage 2 hospitalization death considered unrelated is useful for understanding the endpoint classification, but it is not a reported primary endpoint estimate.

The study’s stated goal includes comparisons with melarsoprol and suramin. However, the design lists no concurrent control group and is explicitly non-randomized. The results therefore cannot be interpreted as a direct randomized comparison with either existing treatment. Any historical comparison would require additional information about the comparison data, populations, measurement, and analysis; those details are not reported in the registry record.

The adverse-event counts describe recorded events in the enrolled stage groups. They do not, on their own, establish that fexinidazole is safer or less safe than another treatment, and the stage groups should not be treated as interchangeable comparator arms. More generally, an observed event count is not a causal estimate. Design, eligibility, outcome definition, follow-up, and completeness of ascertainment all shape what can be inferred.

Thus, the record supports description of the trial’s design, questions, endpoint definitions, and selected safety listings. It does not support a numerical conclusion about the primary endpoint, the treatment-failure outcomes, or comparative efficacy against melarsoprol or suramin from the information reported.

14. Why This Trial Matters Statistically

This trial is statistically notable because it addresses a rare disease setting while separating participants by disease stage and defining a focused primary endpoint for stage 2 disease. The registry records 45 participants overall, including 35 stage 2 patients treated. In studies with limited participant numbers, the amount of information available for uncommon outcomes can be constrained. General statistical reasoning suggests that sparse events often produce uncertain estimates; the numerical confidence interval would be needed to assess that uncertainty for the primary endpoint, but it is not reported in the registry record.

The distinction between the study’s aims and its design is important. The stated questions concern whether fexinidazole outcomes are lower than those associated with existing treatments, but the study is non-randomized and lists no concurrent comparator. Statistical interpretation should not turn a single-treatment study into a causal head-to-head comparison. This is particularly important when treatment groups might differ in disease severity, setting, follow-up, or other prognostic features.

The record also illustrates how endpoint definitions shape results. The primary endpoint counts only deaths assessed as possibly related to r-HAT or treatment and uses an evaluable stage 2 population. A death considered unrelated is excluded from efficacy evaluability, and some patients without a retrievable outcome are also classified as non-evaluable. Clear reporting of these rules, the resulting analysis population, and uncertainty estimates is essential to understanding what a percentage means.

Finally, the study includes multiple efficacy and safety outcomes. Considering the outcome list and analysis count together makes transparent statistical reporting important: readers need to know which analyses were primary, how missing information was handled, and whether multiplicity was addressed. Those details are not reported in the registry record. The trial therefore offers a useful case for distinguishing descriptive safety data, prespecified endpoint definitions, and comparative claims that require a suitable comparison design.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most important limitation for interpreting the posted efficacy information is that the numerical primary endpoint estimate and its 90% confidence interval are not reported in the registry record. Numerical treatment-failure results are also not reported in the available information. This prevents assessment of the magnitude and precision of the principal efficacy outcomes.

The design is non-randomized, open-label, and lists fexinidazole without a concurrent comparator. The study’s stated comparisons with melarsoprol and suramin therefore are not direct randomized contrasts in this record. Differences from outcomes reported elsewhere could reflect patient selection, clinical setting, endpoint definitions, follow-up, or other differences, not only treatment.

The primary endpoint uses an evaluable stage 2 population and excludes certain deaths or unavailable outcomes from efficacy evaluation. The record does not report a full participant flow for each analysis, the number excluded under each rule, or sensitivity analyses for missing outcomes. It also does not report a detailed statistical analysis plan, a sample-size justification, or whether multiplicity adjustments were made, despite listing 11 outcome measures and 6 analyses.

For safety, the registry provides counts by disease stage and selected serious-event terms, but the available information does not give detailed timing, duration, event-level overlap, or a comparative analysis. The stage groups are not treatment comparators, so their counts should be read descriptively. These limitations constrain what can be inferred from the registry record and do not establish either benefit or harm relative to existing treatments.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fexinidazole in Human African Trypanosomiasis Due to T. b. Rhodesiense — NCT03974178.
• Registry record last updated 2025-01-30; status last verified 2024-12.
• Results first posted 2025-01-30.
• 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.

19. Record Summary

The registry describes a completed, multicentre, open-label, non-randomized clinical trial of fexinidazole for r-HAT, listed as phase 2 and phase 3. A total of 45 participants were enrolled. Patients with stage 1 and stage 2 disease received oral fexinidazole for 10 days. The primary endpoint was the percentage of evaluable stage 2 patients who died during hospitalization from causes considered possibly related to r-HAT or fexinidazole, within the period described as 12 to 18 days after treatment began.

The record lists treatment-failure outcomes at the end of hospitalization and at 12 months, mortality outcomes, and adverse-event outcomes. It reports selected safety counts and serious-event terms, but the numerical primary efficacy result, its confidence interval, and numerical treatment-failure results are not reported in the registry record. No concurrent comparator is listed, so the study design does not provide a randomized comparison with melarsoprol or suramin.