Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet (NCT00682630), a randomized phase 1 study. The primary outcome is Pyronaridine Pharmacokinetics: Tmax, Half-life.

2. Clinical Question

Bioequivalence is a comparison of how the body is exposed to, or processes, two formulations. In general, the question is not whether one formulation is superior, but whether the formulations have sufficiently similar pharmacokinetic behavior under the study conditions. The particular measures, comparison method and decision criteria matter to that interpretation. The registry record names Tmax and half-life and describes how half-life was computed, but the statistical comparison and its criteria are not reported.

3. Trial Design

This was a Phase I, randomized, open-label, crossover trial in healthy adults. It compared pyronaridine artesunate to-be-marketed tablets with clinical trial reference tablets. The registry record lists malaria as the condition and Medicines for Malaria Venture as the sponsor. The study began in 2007-09, reached primary completion in 2008-07, and is recorded as completed.

In one sequence, participants received the clinical trial reference tablets on Day 0, followed by a 43-day washout, then the to-be-marketed tablets on Day 43. The other sequence reversed the order: to-be-marketed tablets on Day 0, followed by the clinical trial reference tablets on Day 43. Each administration was a single total dose of 720:240 mg. The record describes a 42-day follow-up period.

A crossover design gives each participant experience with both formulations. In general, this can make a comparison more informative by allowing the analysis to account for differences between people. It also means that the sequence and timing of treatment periods matter: effects from an earlier period could influence a later one if they persist. The registry record specifies the washout interval but does not report whether period or carryover effects were assessed, or how sequence was incorporated into the analysis.

The study was randomized and had no masking. The registry record does not report the randomization method, allocation concealment, or further operational details. It reports enrollment of 42, but does not give a participant flow or explain whether all enrolled participants completed both treatment periods.

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.

First Intervention (Day 0)

Washout (43 Days)

Second Intervention (Day 43)

Follow-up (42 Days)

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic population

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: all subjects who received at least one dose of study drug

6. Primary Endpoint

The registry lists the primary outcome as Pyronaridine Pharmacokinetics: Tmax, Half-life, measured over Sampling performed at predose at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period.

The listed primary outcome is “Pyronaridine Pharmacokinetics: Tmax, Half-life.” Tmax is the time at which the measured concentration reaches its maximum. Half-life describes the time associated with a decline in concentration and, in this record, is described as computed from ln (2)/kel. The outcome is reported as a mean with standard deviation, and the named population is the pharmacokinetic population.

These measures describe different features of the concentration-time profile. In general, Tmax characterizes the timing of the peak, while half-life describes the rate of decline during the relevant part of the profile. Comparing these features can help characterize how two formulations behave after administration. They do not, by themselves, provide every aspect of a pharmacokinetic comparison.

Sampling was scheduled predose at 0 h and at 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period. The registry record does not report the observed Tmax or half-life values, their variability, or a comparison between formulations. It also does not report a bioequivalence decision based on these measures.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization assigns participants to treatment sequences by chance. In this trial, the sequences determined which formulation was taken first and which was taken after the washout. In general, random allocation can reduce systematic differences between sequence groups, although the quality of that protection depends on how allocation was generated and implemented. The registry record does not report the randomization procedure or allocation concealment.

Why use a crossover design?

In a crossover study, each participant receives both treatments at different times. A comparison can then use within-participant information: each person’s measurement under one formulation is considered alongside that person’s measurement under the other. In general, this can reduce the influence of stable differences between participants. It does not remove all uncertainty, and it depends on the timing and conduct of the periods.

The two sequences were reference first and to-be-marketed second, or to-be-marketed first and reference second. The record describes administration on Day 0 and Day 43, with a 43-day washout. A washout is intended to separate treatment periods so that the earlier administration does not affect measurements in the later period. Whether the chosen interval was sufficient for the relevant measurements, and whether carryover was formally assessed, is not reported in the registry record. Period effects and sequence effects can also matter in crossover analyses; the analysis approach for these effects is not reported.

What do the endpoint summaries describe?

The primary outcome is described as a mean with standard deviation. In general, the mean gives a central summary of observed values, while the standard deviation describes their spread around that mean. These summaries are descriptive: they do not, on their own, quantify the uncertainty in a treatment comparison. A standard error or confidence interval for the comparison would address a different question. Neither is reported for the primary outcome.

Tmax and half-life are derived from pharmacokinetic measurements. The record defines Tmax as time to maximum concentration and describes half-life as computed from ln (2)/kel. It provides a sampling schedule for each period, from predose through Day 42. It does not report the concentration data, participant-level derived values, handling of measurements below quantification limits, or details of the pharmacokinetic calculation beyond the stated half-life formula.

What does a bioequivalence analysis require?

In general, a bioequivalence analysis needs a defined comparison, an appropriate statistical model, and prespecified criteria for interpreting the estimate and its uncertainty. The model should reflect the crossover design and the measurements being compared. The record does not report a model, transformation, comparison scale, confidence interval, or decision limits. It names Tmax and half-life, but does not explain how those measures were used to decide bioequivalence. As a result, the intended statistical decision process cannot be reconstructed from the registry record.

A confidence interval is a range of estimates compatible with the observed data under a specified model and its assumptions. For an equivalence question, its position relative to prespecified limits is often central to interpretation. This is a general explanation, not a description of the analysis in this trial: the registry record does not report such an interval or those limits. A p-value alone, even if it were reported, would not substitute for a defined equivalence analysis.

What can planning illustrations tell readers?

The planning illustration is described as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence about the trial’s original design. The record does not report the original sample-size justification or whether the trial was planned using those assumptions. Any sample-size illustration is not observed power and does not establish that the trial could or could not answer its primary question.

The illustration description refers to equal allocation between two arms, whereas the trial itself is recorded as a crossover study. This underscores that a planning illustration should not be confused with the trial’s actual design or a crossover-specific analysis. The registry record does not report the analysis plan needed to connect such a planning calculation to the trial’s primary endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists five outcome measures and notes that the primary outcome has several categories or time points, so it was not reduced to one comparison. It lists zero analyses. The record does not state which outcome comparisons were designated as primary for statistical testing, how multiple measures or time points were handled, or whether any adjustment for multiplicity was planned.

In general, multiplicity arises when several outcomes, time points, or comparisons are examined. Considering many results can increase the chance of finding an apparently notable result by chance. Prespecifying the main comparison and explaining any adjustment helps readers distinguish confirmatory analyses from exploratory ones. Those details are not reported in the registry record, so the strength of any statistical claim cannot be evaluated on that basis.

The primary population is named as the pharmacokinetic population, but its definition and size are not reported. The record does not describe missing measurements, exclusions, withdrawals, protocol deviations, or how incomplete periods were handled. It also does not report whether the analysis included participants according to sequence assignment or only those with usable measurements for both formulations.

In general, missing-data handling matters because the participants with available measurements may differ from those without them. In a crossover trial, missing measurements in either period can also affect whether a within-participant comparison is possible. Without participant flow, missingness details, and analysis-population definitions, it is not possible to assess how these issues affected the reported result. The registry record contains no primary analysis results with which to evaluate them.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry record reports zero serious adverse events among 39 participants in the to-be-marketed tablet group and zero among 40 participants in the clinical trial reference tablet group. It also reports zero deaths in each group. For other adverse events, the record lists 26 affected participants among 39 at risk with the to-be-marketed tablets, and 28 among 40 at risk with the clinical trial reference tablets.

These are the recorded counts and denominators. The registry record does not describe the event terms, severity grading beyond the serious-event classification, timing, relatedness assessment, or how events were attributed across the two treatment periods. It also does not explain why the safety denominators differ from the enrollment count.

In general, a count of zero serious events in a group does not establish that the risk is absent; it describes what was recorded in that group during the period covered by the safety reporting. The other-adverse-event counts do not, by themselves, establish a difference between formulations. The registry record does not report a statistical safety comparison or enough detail to interpret event types and exposure periods.

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

The registry record describes a randomized crossover comparison of two pyronaridine artesunate tablet formulations, together with a pharmacokinetic sampling schedule and safety counts. It identifies the primary outcome as Tmax and half-life in the pharmacokinetic population. These details establish what the study set out to compare and how measurements were scheduled, but they do not show the observed primary outcome results.

Because numerical pharmacokinetic results, comparison estimates, and uncertainty intervals are not reported, the record does not establish whether the formulations met a bioequivalence criterion. It also does not report the statistical criteria or analysis used to reach such a decision. Neither the trial’s randomized crossover design nor its completion status can substitute for those results.

The record’s safety figures describe zero serious adverse events and zero deaths in each listed group, alongside counts for other adverse events. Those figures should be interpreted as recorded counts for the stated denominators, not as a complete account of all possible safety outcomes or as proof of no risk. Event descriptions and comparative analyses are not reported.

In general, trial findings apply most directly to the population, interventions, and study conditions examined. This study involved healthy adults and single-dose administration, as described in the record. The record does not report outcomes that would support conclusions about other populations, longer-term use, or clinical outcomes. The clinical question is pharmacokinetic bioequivalence, not whether either formulation improves health outcomes.

The most defensible reading is therefore limited: the registry documents the design, intended pharmacokinetic measures, timing of sampling, and selected safety counts. It does not provide the numerical primary results or the analysis details needed to judge the central bioequivalence question.

13. Why This Trial Matters Statistically

This trial is statistically notable for its crossover design. When both formulations are given to the same participants in separate periods, the comparison can use within-person measurements rather than relying only on differences between separate groups. In general, this can be useful for pharmacokinetic questions, where participant-level variation may be important. The design also makes sequence, period, washout, and completeness of both treatment periods relevant to interpretation.

The registry record gives the sequence structure, the 43-day washout, and a detailed sampling schedule for each period. These features help describe how the comparison was organized. They do not reveal whether the observed measurements were complete or how the statistical analysis accounted for the crossover structure. Those analysis details are not reported.

The record also illustrates why a trial’s stated objective and its posted results are distinct. The objective is to determine bioequivalence, and the endpoint names pharmacokinetic measures relevant to that objective. But without estimates, uncertainty, and decision criteria, readers cannot evaluate whether the objective was achieved. A design can be appropriate to a question while the available record remains insufficient to answer it.

Finally, the posted safety counts require careful attention to denominators and reporting scope. The safety groups have different participant counts, and the registry record does not explain the discrepancy from enrollment. Keeping the reported population, endpoint, and analysis details distinct is essential for a sound statistical reading.

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 main limitation of the registry record for statistical interpretation is the absence of numerical primary outcome results. Although the outcome is named and the sampling schedule is detailed, the record does not report observed Tmax or half-life values, a comparison estimate, or its uncertainty. It also does not report the criteria used to determine bioequivalence.

Further analysis details are not reported in the registry record. These include the statistical model, the treatment comparison scale, the handling of period and sequence effects, and whether carryover was assessed. The record does not state how measurements were processed beyond the half-life definition, or how incomplete pharmacokinetic data were handled.

The record identifies the pharmacokinetic population but does not define it or report its size. It gives enrollment of 42 and safety denominators of 39 and 40, but does not describe participant flow or explain the differences. Missing measurements, withdrawals, exclusions, and protocol deviations are not reported.

The study is described as Phase I and conducted in healthy adults with single-dose administration. The registry record does not provide outcome information for other populations, repeated administration, or clinical endpoints. These are limits on what this record can establish, rather than evidence about results that are not posted. The listed safety counts also lack event descriptions and a reported comparative analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet — NCT00682630.
• Registry record last updated 2023-02-03; status last verified 2023-02.
• Results first posted 2023-02-03.
• 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

This completed Phase I trial randomized 42 healthy adults to one of two treatment sequences in a crossover comparison of to-be-marketed pyronaridine artesunate tablets and clinical trial reference tablets. Each formulation was administered as a single total dose of 720:240 mg, with a 43-day washout between periods.

The primary outcome was pyronaridine Tmax and half-life in the pharmacokinetic population. Sampling was scheduled from predose through Day 42 in each period. The registry record does not report numerical primary outcome results, a statistical comparison, or a bioequivalence conclusion.

Safety reporting lists zero serious adverse events and zero deaths in each group, with other adverse events recorded for 26 of 39 and 28 of 40 participants, respectively. Reasons for the safety denominators and further event details are not reported in the registry record.