Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria (NCT00440999), a randomized phase 3 study. The primary outcome is Crude Cure Rate on Day 14.

2. Clinical Question

3. Trial Design

This was a Phase III, randomized, double-blind, double-dummy, parallel-group, multicentre study. It compared oral pyronaridine artesunate with oral chloroquine in children and adults with acute vivax malaria. The registry lists enrollment of 456 participants and a completed status. The recorded start was 2007-03 and primary completion was 2008-04.

Random allocation is intended to make treatment groups comparable, on average, with respect to both measured and unmeasured baseline characteristics. It does not guarantee that every characteristic will be balanced in a particular trial. The registry record does not report the randomization sequence method, allocation concealment procedure, or stratification factors, so those details cannot be assessed.

Double-dummy masking is used when the treatments being compared differ in their presentation or dosing. Participants in each group can receive an active treatment and a matching placebo, helping preserve masking despite differing tablet regimens. The record identifies the study as double-blind and double-dummy, but does not report which roles beyond participants and investigators were masked or how masking success was assessed.

The treatment regimens differed in dose and schedule. Pyronaridine artesunate was administered once daily for 3 days, with the number of tablets depending on body weight. Chloroquine dosing differed for adults and children and was spread over Days 0, 1 and 2. These are the recorded regimens; adherence beyond the eligibility conditions for the efficacy-evaluable population is not reported in the registry record.

The registry lists secondary outcomes including crude cure rate on Days 21 and 28, parasite clearance time, fever clearance time, clearance percentages on Days 1, 2 and 3, and participants with adverse events. The analysis plan, handling of multiple outcomes, and the detailed statistical methods are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

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: Safety population, defined as all randomized subjects who received any amount of study medication. Males/Females between ages of 3 and 60 years, with body weight ≥ 20 kg.

6. Primary Endpoint

The registry lists the primary outcome as Crude Cure Rate on Day 14, measured over Day 14.

The primary endpoint was crude cure rate on Day 14, reported as a count of participants. Cure required absence of P. vivax parasitaemia on Day 14, regardless of temperature, and no prior treatment failure during follow-up. This definition combines a status at a specified assessment day with a condition on the participant’s earlier course: a participant who had already met a treatment-failure criterion would not qualify as cured under the stated definition.

In general, a binary endpoint classifies each participant into one of two outcome states, such as cured or not cured under a specified definition. Counting participants in each state allows a treatment comparison to be expressed as a difference or ratio of cure probabilities, provided the required group counts and analysis details are available. The registry record does not report those primary outcome counts or an effect estimate, so no numerical comparison of the cure rates can be made.

A fixed assessment day gives the outcome a clear time point and can make the endpoint clinically interpretable. At the same time, the result depends on the endpoint definition, follow-up procedures, and the population included in the analysis. The efficacy-evaluable population excluded participants with specified protocol-related circumstances, including missed doses and some concomitant medicines or diseases. How participants excluded from that population were handled in other analyses is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary endpoint represent?

The primary endpoint is a participant count for a defined binary outcome: cure on Day 14 or failure to meet that cure definition. In general, a binary analysis compares the proportion of participants meeting the outcome in each group. An absolute contrast expresses the difference between those proportions, while a relative contrast compares them as a ratio. Both depend on the selected population, the outcome definition, and the way missing or unevaluable observations are handled. The registry record does not report the Day 14 outcome counts, effect estimate, or primary endpoint analysis method.

The endpoint definition matters because cure was not simply a parasite measurement on Day 14. The participant also had to avoid having previously met a treatment-failure criterion during follow-up. The endpoint therefore draws on information across follow-up as well as the Day 14 assessment. The individual treatment-failure criteria and their adjudication procedures are not reported in the registry record.

Why does randomization matter?

General statistical principle: randomization supports a fair comparison by assigning treatment independently of participants’ prognosis, on average. It reduces the risk that treatment selection is systematically related to outcome. Randomization does not eliminate chance imbalances, measurement error, loss to follow-up, or bias introduced after allocation. The record identifies the study as randomized but does not describe sequence generation, concealment, stratification, or baseline comparability.

The registry identifies the design as double-blind and double-dummy. General principle: masking can reduce the risk that knowledge of treatment assignment affects participant behavior, clinical management, outcome assessment, or reporting. A double-dummy approach can help maintain masking when active regimens differ in how they are taken. The record does not report masking assessments, details of who remained masked, or whether masking was broken.

What can confidence intervals and p-values tell readers?

General explanation: a confidence interval describes the statistical uncertainty around an estimated effect under the analysis assumptions. A narrower interval indicates greater precision than a wider interval, but precision does not by itself establish clinical importance. A p-value measures how surprising the observed data, or more extreme data, would be under a specified null model. It is not the probability that the null hypothesis is true, nor a measure of effect size. Neither a confidence interval nor a p-value for the primary cure-rate comparison is reported in the registry record.

For a binary endpoint, the statistical method should be suitable for comparing outcome proportions and should state how it treats the analysis population and missing outcomes. Adjustment for baseline factors, if used, can affect the estimate and its uncertainty. The registry record does not report whether the primary analysis was adjusted, which statistical test or model was used, or what confidence level was planned.

How should the safety counts be understood?

General principle: safety counts describe the recorded events or participants meeting an event definition, and their meaning depends on the denominator, observation period, and coding rules. Serious adverse events are not interchangeable with all adverse events. A count alone does not establish causality, and a zero count does not prove that an event cannot occur. The registry reports serious-event counts and deaths by group, but does not report event narratives, exposure-adjusted rates, or an inferential comparison.

Over-dispersion is relevant to some count-data analyses. General explanation: it occurs when observed variation in counts exceeds the variation assumed by a simple model, which can make standard errors too small if ignored. The posted primary outcome is a participant count for a binary endpoint, not a reported repeated-event count model. The registry record does not report an over-dispersion assessment or count-model analysis, so no such method can be attributed to this trial.

What do planning illustrations mean?

General explanation: sample-size planning asks how many participants would be needed under specified assumptions to detect a chosen effect with a chosen error rate and power. A planning illustration based on an observed effect is not the trial’s original design justification and is not observed power. The record describes an illustration using a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as stated fractions of the observed effect. For non-time-to-event outcomes, its convention is participants per arm; for time-to-event outcomes, the convention is total events. No planning values or original sample-size justification are reported in the registry record, and the absent primary cure results prevent interpretation of an observed-effect-based illustration for that endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and several secondary outcomes, including cure at later days, parasite and fever clearance measures, and adverse events. Testing several outcomes or time points can increase the chance of at least one false-positive finding if each is assessed independently. General statistical approaches include designating a single primary comparison, adjusting significance thresholds, or using a prespecified testing sequence. The registry record does not report a multiplicity strategy, whether secondary outcomes were confirmatory or exploratory, or how repeated assessments were handled.

The primary analysis population was efficacy evaluable, with specified conditions concerning treatment completion, missed doses, potentially interfering concomitant medicines, and concomitant disease. The registry record does not report how many participants met those criteria, how missing Day 14 assessments were treated, or whether participants outside that population were included in a different primary analysis. It also does not report a missing-data method or sensitivity analysis.

These details matter because excluding participants after randomization can affect the comparability created by random assignment. General principle: an analysis based on all randomized participants, when appropriately defined, can preserve the randomized comparison, while an evaluable-population analysis may answer a narrower question about participants meeting specified conditions. The registry record does not report an intention-to-treat analysis or clarify how it relates to the efficacy-evaluable analysis.

The registry lists one analysis and nine outcome measures, but does not give the statistical plan, analysis hierarchy, or endpoint-specific denominators. The primary outcome results are not reported in the registry record. As a result, neither the handling of missing data nor the impact of multiple outcome assessments can be evaluated from the posted information.

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: pyrexia (0.4%), typhoid fever (0.4%).

The safety record lists 228 participants at risk in each group. Serious adverse events were recorded for 2 participants receiving pyronaridine artesunate and 0 receiving chloroquine. Deaths were listed for 2 and 0 participants, respectively. The record also names pyrexia and typhoid fever among the top serious-event terms, each reported as 0.4%.

These are descriptive counts, not evidence by themselves that treatment caused or prevented an event. The registry record does not report the timing, clinical details, relatedness assessments, or group attribution for the named serious-event terms. It also does not clarify whether deaths are included among the serious adverse-event counts, so the categories should not be added together or assumed to be distinct.

The “other” adverse-event counts were 90 with pyronaridine artesunate and 72 with chloroquine. The precise event category and counting rule are not reported in the registry record. These counts should therefore be interpreted within the registry’s labels and not treated as an independently verified rate comparison. No statistical test or uncertainty estimate for safety differences is reported.

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

The registry record establishes the study question, design, treatment regimens, Day 14 cure definition, and several safety counts. It identifies a randomized, double-blind, double-dummy comparison in children and adults with acute vivax malaria and records enrollment of 456 participants. These details make clear what comparison was intended, but do not reveal the comparative primary efficacy result.

The primary endpoint results are not reported in the registry record. In particular, there are no Day 14 cure counts by group, no primary effect estimate, and no confidence interval or p-value. Therefore, the posted information does not show the magnitude, direction, or precision of any difference in cure rate between pyronaridine artesunate and chloroquine. It does not support a conclusion about whether one treatment had a higher cure rate.

The serious adverse-event and death counts provide a limited descriptive account. They are not a substitute for a complete safety analysis and do not establish causality. The “other” adverse-event figures also lack sufficient category detail to determine exactly what was counted. Interpretation would require clearer event definitions, participant-level context, follow-up duration, and analysis procedures, none of which are reported in the registry record.

General statistical principle: absence of a reported estimate is not evidence that the true treatment effects are equal. It means the posted record does not provide the information required to quantify the comparison. Likewise, a count of zero observed events does not establish zero underlying risk. A reader should distinguish what the registry documents from conclusions that would require outcome results and a prespecified analysis.

The record also does not report the original sample-size justification, detailed statistical plan, missing-data handling, or multiplicity approach. Those omissions limit assessment of how the trial was designed to answer its primary question and how robust any eventual result would be. The registry entries available support a description of the trial, but not a numerical efficacy conclusion.

13. Why This Trial Matters Statistically

This trial raises several important statistical issues for interpreting clinical comparisons. Its randomized design is intended to support treatment-group comparability, while its double-blind, double-dummy approach addresses the challenge of comparing regimens with different schedules and presentations. These design features are relevant to bias control, but their practical implementation and assessment are not reported in the registry record.

The primary endpoint is a binary cure outcome with a defined Day 14 assessment and a condition relating to previous treatment failure. Such endpoints can be understandable and clinically interpretable, but they depend on explicit outcome criteria and consistent assessment. The registry gives the main cure definition, while detailed failure criteria and adjudication procedures are not reported.

The efficacy-evaluable population also illustrates why analysis populations matter. Eligibility for that population depended on completing treatment and avoiding specified circumstances that could interfere with outcome classification. Without participant counts and a clear account of all randomized participants, readers cannot judge how population exclusions may have affected the comparison.

Finally, the registry record shows how design details and outcome evidence are not interchangeable. Enrollment and safety counts do not supply the missing primary cure results. Statistical interpretation requires the outcome counts or estimates, their uncertainty, and enough information about the analysis to understand what was compared. In this record, those primary efficacy results and much of the analysis plan are not reported, so the central treatment comparison remains unquantified.

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.

A central limitation is that primary outcome results are not reported in the registry record. There are no Day 14 cure counts, group-specific efficacy denominators, treatment-effect estimate, confidence interval, or p-value. The primary comparison therefore cannot be independently interpreted from the registry information.

The primary endpoint was analyzed in an efficacy-evaluable population defined by treatment completion and other conditions. The record does not give the number of participants meeting those criteria or explain how participants who did not meet them were treated in other analyses. It also does not report missing Day 14 outcome handling or sensitivity analyses.

Important design and analysis details are absent, including the randomization procedure, allocation concealment, statistical method, adjustment factors, multiplicity strategy, and original sample-size justification. The detailed criteria for treatment failure are not reported. These omissions limit assessment of bias control, endpoint classification, and analysis robustness.

The safety information is also limited. Serious adverse events and deaths are given as counts, but event timing, descriptions, attribution, and whether the categories overlap are not reported. The meaning of the “other” adverse-event counts is not further specified. The named serious-event terms lack group-specific context in the record.

The enrollment and adverse-event denominators do not establish the denominators used for the efficacy analysis. The record lists secondary outcomes but does not provide their results or explain how multiple endpoints and time points were handled. These gaps constrain interpretation to the stated design and descriptive safety details rather than a full appraisal of efficacy or safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria — NCT00440999.
• Registry record last updated 2021-11-02; status last verified 2021-10.
• Results first posted 2021-09-20.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes a completed Phase III randomized, double-blind, double-dummy, parallel-group, multicentre study comparing oral pyronaridine artesunate with chloroquine in children and adults with acute vivax malaria. Enrollment was 456. The recorded start was 2007-03 and primary completion was 2008-04.

The primary endpoint was crude cure rate on Day 14 in an efficacy-evaluable population. Cure required absence of P. vivax parasitaemia on that day, regardless of temperature, without a prior treatment-failure criterion. Primary cure results and detailed statistical methods are not reported in the registry record.

For safety, the record lists serious adverse events in 2 participants with pyronaridine artesunate and 0 with chloroquine, deaths of 2 and 0, and other adverse-event counts of 90 and 72. Each group had 228 participants at risk. The available safety counts are descriptive and lack detailed event context.