Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria (NCT01594931), a randomized phase 2 study. The primary outcome is PCR-Corrected ACPR at Day 28.

2. Clinical Question

3. Trial Design

This was a randomized, triple-masked, parallel-group Phase II dose-ranging study. Its official title describes a multicentre study of fixed-dose, orally administered pyronaridine and artesunate in adults with acute uncomplicated Plasmodium falciparum malaria. The registry record reports enrollment of 477. The study started in 2005-07, reached primary completion in 2006-03, and is listed as completed.

Participants were assigned to one of three pyronaridine/artesunate dose groups: 6:2 mg/kg, 9:3 mg/kg, or 12:4 mg/kg. The trial summary describes a 3:1 combination and once-daily dosing for 3 days. The primary efficacy comparisons use the 6:2 mg/kg group as the reference and compare it separately with each higher dose group. This reference role does not make the group a placebo or an untreated control; the registry record identifies all three groups as receiving pyronaridine/artesunate.

The stated primary objective was to determine a clinically effective dose for adults with acute, symptomatic, uncomplicated malaria in South East Asia and Africa. Secondary objectives included assessing safety and exploring possible ethnic differences in safety or efficacy. The registry record does not report the actual allocation ratio, the masking procedures, the countries or sites, or results for ethnic subgroups. It also does not report the original sample-size justification or the trial’s prespecified statistical analysis plan.

The primary endpoint results are drawn from a defined efficacy population rather than all enrolled participants. To qualify, subjects had to complete the full study-medication course and have known efficacy endpoints, with additional restrictions on vomiting-related missed doses, concomitant medication, concomitant disease, and major protocol violations. That population definition matters when interpreting the endpoint: its denominator is not the overall enrollment, and the registry record does not describe how participants outside that population were handled in every analysis.

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: Subjects meeting the following: completed a full course of study medication and had known efficacy endpoints; no missed dose due to vomiting (except at D0); no concom. medication, except acetaminophen; no concom. disease that could have interfered with treatment outcome; no major protocol violation with respect to entry eligibility criteria.

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.

6. Primary Endpoint

The registry lists the primary outcome as PCR-Corrected ACPR at Day 28, measured over Day 28.

The primary endpoint is PCR-corrected adequate clinical and parasitological response (ACPR) at Day 28, reported as a percentage of subjects. A subject counted as a responder had to have no parasitaemia on Day 28 and had to avoid the specified criteria for early treatment failure, late clinical failure, and late parasitological failure. This combines a parasitological finding at a defined follow-up time with clinical and parasitological failure criteria during the treatment assessment.

PCR correction is intended, in general, to distinguish recurrent parasitaemia associated with the original infection from a new infection. The registry record names the endpoint as PCR-corrected but does not report the laboratory procedures or classification rules used for that correction. The result should therefore be read as the posted endpoint definition and not as a complete description of how the molecular correction was performed.

A percentage endpoint makes it possible to compare the proportion of the eligible efficacy population meeting the response definition across dose groups. Day 28 provides a stated time point for assessing whether parasitaemia is absent after treatment. The endpoint is relevant to the trial’s dose-selection objective because it summarizes response under each assigned dose, while the failure criteria prevent a Day 28 result from being interpreted in isolation from specified earlier treatment failures.

The endpoint does not, by itself, describe every aspect of clinical course or safety. Clearance times and adverse events are listed separately as secondary outcomes. Nor does the response percentage establish what difference would be clinically important: such a threshold is not reported in the registry record.

7. Results Posted in the Registry

• Group B: Pyronaridine/Artesunate (9:3 mg/kg): 99.0% (102/103) versus 95.0% (96/101) on control; risk difference 4.0 percentage points (95% CI -0.7 to 8.6), risk ratio 1.04 (0.99–1.09); unadjusted two-proportion z-test p = 0.093.
• Group C: Pyronaridine/Artesunate (12:4 mg/kg): 99.0% (101/102) versus 95.0% (96/101) on control; risk difference 4.0 percentage points (95% CI -0.7 to 8.6), risk ratio 1.04 (0.99–1.09); unadjusted two-proportion z-test p = 0.095.

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

• 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 deviations.
• Result:
  • Group B: Pyronaridine/Artesunate (9:3 mg/kg): mean 33.60 versus 36.90 on control; difference -3.30 (95% CI -8.36 to 1.76), standardized effect d = -0.17; z-test p = 0.201.
  • Group C: Pyronaridine/Artesunate (12:4 mg/kg): mean 30.80 versus 36.90 on control; difference -6.10 (95% CI -10.91 to -1.29), standardized effect d = -0.34; z-test p = 0.013.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group B: Pyronaridine/Artesunate (9:3 mg/kg) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Group C: Pyronaridine/Artesunate (12:4 mg/kg) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Fever Clearance Time

• 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 deviations.
• Result:
  • Group B: Pyronaridine/Artesunate (9:3 mg/kg): mean 24.00 versus 16.80 on control; difference 7.20 (95% CI 1.26 to 13.14), standardized effect d = 0.35; z-test p = 0.018.
  • Group C: Pyronaridine/Artesunate (12:4 mg/kg): mean 17.00 versus 16.80 on control; difference 0.20 (95% CI -3.58 to 3.98), standardized effect d = 0.02; z-test p = 0.917.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Group B: Pyronaridine/Artesunate (9:3 mg/kg) 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 Group C: Pyronaridine/Artesunate (12:4 mg/kg) and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the picture beyond the Day 28 response percentage. The registry lists parasite clearance time, fever clearance time, parasite clearance, fever clearance, and adverse events among its secondary measures. The posted numerical comparisons described in detail include mean parasite clearance time and mean fever clearance time. Together, these measures address early changes in parasitaemia and fever, while the primary endpoint captures a later response definition.

The secondary pattern is not uniformly aligned across outcomes or dose comparisons. Some clearance-time point estimates move toward shorter parasite clearance with higher dose, while the fever-clearance summaries do not follow the same dose ordering. The uncertainty around the recalculated comparisons also varies. This means that a single secondary endpoint should not be treated as a complete explanation of the primary response pattern. The measures describe related but distinct aspects of response.

These outcomes are secondary and the registry record reports no sponsor analyses for them. The displayed p-values are unadjusted recalculations, and the record does not state how the trial’s investigators handled multiple comparisons. General statistical explanation: when many outcomes and comparisons are examined, the chance of at least one apparently notable result due to random variation can increase. Without a reported multiplicity strategy, isolated secondary p-values warrant more caution than a prespecified primary analysis.

Secondary findings can be useful for understanding consistency, timing, and possible patterns that merit further study. They do not replace the primary endpoint, establish a dose-selection rule, or show that a difference is clinically meaningful. No prespecified threshold for meaningful changes in clearance time is reported. Likewise, results for the other listed secondary measures are not detailed in the registry record, so they cannot be used to infer a complete pattern across every secondary outcome.

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

• PCR-Corrected ACPR at Day 14
• Parasite Clearance Time
• Fever Clearance Time
• Parasite Clearance
• Fever Clearance
• Adverse Events (AEs)

9. Statistical Interpretation

10. Statistical Methods Explained

How should the response percentages be read?

The primary endpoint is binary at the participant level: each eligible subject either meets the stated Day 28 response definition or does not. The posted group value is the percentage of subjects meeting that definition, and the accompanying 90% confidence interval conveys uncertainty around the group percentage. General statistical explanation: a confidence interval describes a range of values compatible with the data under the method used; it does not mean that a fixed share of individual participants had outcomes within the interval.

The endpoint’s denominator is restricted to the efficacy population described in the registry record. It excludes subjects who did not meet the stated completion and endpoint-availability conditions, as well as specified protocol-related restrictions. The record gives group denominators for the primary endpoint, but it does not report a full participant flow or a detailed account of missing endpoint data.

What does the risk difference add?

The recalculated comparisons express the difference between two response percentages on an absolute scale. A positive estimate means the percentage was higher in the named dose group than in the 6:2 mg/kg reference group. For each comparison, the associated interval spans values on both sides of zero. General statistical explanation: zero represents no absolute difference; an interval that includes zero is compatible with no difference as well as with differences in either direction.

The registry record also includes recalculated relative measures, the risk ratio and odds ratio. These describe the comparison on different scales, and their intervals are broad. General statistical explanation: relative measures can be less intuitive than absolute differences, particularly when the event being counted is common. The posted estimates should be interpreted with their uncertainty rather than by focusing on a single point estimate. No clinical threshold for interpreting any of these scales is reported.

How should p-values be understood?

The unadjusted p-values attached to the primary pairwise comparisons are recalculations from posted summary data. General statistical explanation: a p-value describes how incompatible the observed data are with a specified no-difference model, under the assumptions of the test. It is not the probability that the no-difference model is true, nor does it measure the size or importance of an effect. Because the registry record does not report the sponsor’s comparative analysis or its testing procedure, these p-values should not be treated as a reproduction of the trial’s formal analysis.

The trial record lists no posted analyses for the secondary outcomes. For the two continuous secondary outcomes with group means, recalculated comparisons use the mean difference and report intervals and unadjusted p-values. General statistical explanation: a mean difference is expressed in the outcome’s units, while a standard deviation describes variation among observed values. The recorded parasite-clearance and fever-clearance times are in hours. These summaries do not provide the underlying distributions, and the registry record does not report whether the sponsor used a different model or adjusted analysis.

Why do the clearance-time summaries need context?

Parasite clearance time is summarized as a mean with a standard deviation. Its timeframe states that thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded. Fever clearance time is also summarized as a mean with a standard deviation, with measurements every 8 hours for at least 72 hours after the first dose. The observed group sizes for these outcomes differ from the primary endpoint group sizes, so their results concern outcome-specific analysis populations.

General statistical explanation: means and standard deviations are most informative when considered with the shape of the data and the analysis population. If observations are highly skewed or have influential values, the mean may not describe a typical participant well. The registry record does not report distributional diagnostics, transformations, or alternative summaries. No time-to-event analysis is posted for these outcomes; the registry record presents the outcomes as mean clearance times.

What is not specified about the statistical plan?

The registry record does not report the trial’s original statistical analysis plan, the planned handling of multiplicity, the original sample-size justification, or whether interim analyses were conducted. The stated planning assumptions attached to the retrospective sample-size illustrations are separate from those original design decisions. General statistical explanation: prespecification helps distinguish planned analyses from exploratory comparisons and clarifies how uncertainty and multiple testing are handled. Without the trial’s analysis plan, the recalculated comparisons should be regarded as descriptive statistical context rather than as a complete account of the sponsor’s analysis.

These methods explain the posted estimates and their limits; they do not supply unreported modeling choices. The discrepancy flag is false, so the record does not indicate that the sponsor’s own analysis conflicts with the recalculations. Even so, the sponsor’s own analysis takes precedence if a discrepancy is identified, and the formal sponsor analysis is not reported in the registry record.

11. Confidence Intervals and Precision

The group-specific primary endpoint estimates have 90% confidence intervals. For 6:2 mg/kg, the response percentage is 95.0%, with an interval from 89.9% to 98.0%. For 9:3 mg/kg, it is 99.0%, with an interval from 95.5% to 100.0%. For 12:4 mg/kg, it is 99.0%, with an interval from 95.4% to 99.9%. The interval widths show that the estimates are not exact, even though the point estimates are high.

The recalculated risk-difference intervals are also important for precision. The interval for 9:3 mg/kg compared with 6:2 mg/kg runs from -0.007 to 0.086; for 12:4 mg/kg compared with 6:2 mg/kg it runs from -0.007 to 0.086. Both include zero. These ranges are compatible with no absolute difference, as well as with a positive difference for the higher-dose group. The registry record does not state the confidence level for these recalculated comparison intervals, so they should not be assigned a confidence level that is not reported.

General statistical explanation: precision depends on the amount of information in the analysis and on how variable or uncommon the outcomes are. A high response percentage does not automatically imply a precise comparison; when responses are common in all groups, the number of non-responses can be limited, making differences harder to estimate precisely. The analysis denominators are the subjects meeting the endpoint population definition, not the overall enrollment.

Intervals describe statistical uncertainty under the method used, not all possible sources of uncertainty. They do not account for unreported analysis choices, missing-data assumptions, or clinical judgments about meaningful differences. Since no clinically important difference threshold is reported, the intervals cannot by themselves determine whether the possible differences matter in practice.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on observed effects, not the trial’s original design calculations. For these outcomes, the reported figures are participants per arm; the general convention stated for the illustrations is that time-to-event results would instead be total event counts. No time-to-event sample-size result is listed among the comparisons. The original trial sample-size assumptions and justification are not reported in the registry record.

The planning illustrations assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They consider an effect equal to 100% of the observed effect, 75% of the observed effect, or 50% of the observed effect. The 80% power column describes the participants per arm that the illustration estimates would be needed for an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding participants per arm for a 90% chance.

Smaller target effects require more participants per arm in these illustrations. For example, planning for 75% or 50% of the observed effect uses larger per-arm figures than planning for the full observed effect. This is a general feature of power calculations: a smaller difference is harder to distinguish from random variation, so more information is needed to detect it with the same target power.

These numbers are not observed power. They are prospective planning illustrations derived from observed effect estimates and stated assumptions; they do not measure the probability that the completed trial detected an effect. They should not be read as evidence that the original trial was designed with these assumptions, or as a retrospective judgment about whether the trial was adequately powered.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.950; treatment proportion p₁ = 0.990; average p̄ = 0.970.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2397 = 0.4698.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2381 = 0.2003.
4. n = (0.4698 + 0.2003)² / (0.0398)² = 283.6, rounded up to 284 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.95049504950495                          # control proportion
p1 <- 0.990291262135922                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1594931)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 284 (80% power), 380 (90% power)
 75% of observed effect: n per arm = 588 (80% power), 786 (90% power)
 50% of observed effect: n per arm = 1,506 (80% power), 2,015 (90% power)
power.prop.test: 283.6 
Simulated power at n = 284 per arm: 0.846 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and multiple secondary outcomes, along with pairwise comparisons of the two higher-dose groups against the 6:2 mg/kg reference group. It does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a prespecified sequence for interpreting the comparisons. The reported comparison p-values are unadjusted recalculations. They should therefore be read as exploratory statistical context, not as evidence that the trial’s entire family of comparisons was controlled at a particular overall error rate.

General statistical explanation: testing several outcomes or contrasts can increase the chance of obtaining at least one apparently strong result through random variation. Adjustment procedures and prespecified testing hierarchies are ways to address that issue, but the registry record does not say whether such procedures were planned or used. Their absence from the record does not prove that they were not used; it means the approach is not reported in the registry record.

The primary endpoint population is explicitly restricted to subjects who completed a full course of study medication and had known efficacy endpoints, and who met the stated restrictions on vomiting-related missed doses, concomitant medication, concomitant disease, and major protocol violations. This definition is important because the estimated response applies to that analysis population. The registry record does not report whether other analysis populations were used, such as an analysis including all randomized participants, or whether the same eligibility restrictions applied to secondary outcomes.

Although group denominators are posted for the primary and clearance-time outcomes, a complete account of missing data is not reported. The record does not describe reasons for missingness, imputation, sensitivity analyses, or the handling of participants with unknown outcomes. It also does not report whether exclusions were determined before outcomes were examined. These omissions limit assessment of how robust the results are to missing outcomes and population selection. The registry record does not report interim analyses or the sponsor’s full statistical analysis plan, so neither should be assumed.

15. 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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: urinary tract infection (0.6%), hepatic enzyme increased (0.6%), abortion incomplete (0.6%), cardiac failure (0.6%), abscess limb (0.6%).

The serious adverse event counts are reported with group-specific numbers at risk: 160 for the 6:2 mg/kg group, 157 for the 9:3 mg/kg group, and 159 for the 12:4 mg/kg group. The corresponding serious adverse event counts are 3, 0, and 1. No deaths are reported in any of the three groups. These safety denominators differ from the primary efficacy denominators, so the safety counts should not be interpreted as if they came from the restricted efficacy population.

The registry lists urinary tract infection, hepatic enzyme increased, abortion incomplete, cardiac failure, abscess limb, and malaria among the top serious adverse event terms, each reported as 0.6%. Those terms are listed without a group-specific breakdown in the record. The figures describe reported events in this trial; they do not by themselves establish that an event was caused by treatment or allow a comparison of risk between groups.

General statistical explanation: serious adverse events are often uncommon, so a small observed count provides limited precision about their underlying frequency. The registry record does not report event narratives, timing, relatedness assessments, or a formal comparative safety analysis. The absence of reported deaths does not establish absence of other harms.

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

The posted primary results describe high Day 28 PCR-corrected ACPR percentages across all three pyronaridine/artesunate dose groups in the defined efficacy population. The higher-dose groups have higher point estimates than the 6:2 mg/kg group, but the recalculated risk-difference intervals include zero. The evidence in the posted summaries therefore does not clearly distinguish the response percentages between the dose groups. It also does not show that the groups are equivalent, because no equivalence margin or equivalence analysis is reported.

The comparisons are between dose levels of the same combination treatment. They do not establish how any dose compares with placebo, no treatment, or another antimalarial, since such a comparator is not described in the registry record. Nor do the estimates alone identify the clinically effective dose: the record does not state a numerical threshold for clinical importance or report a formal sponsor dose-selection analysis.

The primary endpoint reflects a specific PCR-corrected response definition at Day 28 and a restricted efficacy population. It does not capture every dimension of treatment response, including the full course of clearance, longer-term outcomes, or all safety considerations. The secondary clearance-time estimates and adverse event counts add context, but their interpretation is limited by unadjusted recalculations, varying outcome populations, and the lack of a reported multiplicity strategy and full analysis plan.

These findings are statistical descriptions of the registry record, not medical advice. They should not be read as a recommendation for a particular dose or as proof that a treatment works or does not work. The trial’s Phase II dose-ranging purpose, endpoint definition, uncertainty intervals, and unreported analysis details all matter when considering what can be concluded from the posted results.

17. Why This Trial Matters Statistically

This trial illustrates why dose-ranging results need to be interpreted through both endpoint estimates and their uncertainty. A pattern of high response percentages across dose groups can appear straightforward at first glance, yet comparative estimates show the range of differences compatible with the data. Reporting both group-specific intervals and absolute risk differences helps prevent a point estimate from being mistaken for a precise or definitive dose effect.

The endpoint also makes the analysis population visible as an important part of interpretation. The primary result is not calculated from every enrolled participant; it uses subjects who met the specified completion, endpoint availability, and protocol-related criteria. That distinction affects what population the estimate describes and highlights the value of reporting participant flow and missing-data methods alongside outcome summaries.

The trial also places several statistical questions side by side: a primary binary response, continuous clearance-time outcomes, and serious adverse event counts. These outcomes have different meanings and different sources of uncertainty. A single p-value or a single endpoint cannot summarize all of them. Unadjusted secondary comparisons may suggest patterns, but multiplicity and the absence of the sponsor’s analysis details limit their evidential weight.

Finally, retrospective planning illustrations show how sample-size needs depend on the effect a future study aims to detect. They are distinct from the original trial’s design rationale, which is not reported. Keeping that distinction clear prevents observed results from being mistaken for proof that a trial was planned to detect a particular difference. The record is therefore a useful example of reading dose-ranging evidence with attention to endpoint definition, population, precision, multiplicity, and the limits of registry reporting.

18. 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.

Several trial-specific limitations affect interpretation. First, the primary response analysis uses a restricted population defined by study-medication completion, known efficacy endpoints, and additional restrictions on vomiting-related missed doses, concomitant medication, concomitant disease, and major protocol violations. The registry record does not provide a full participant flow or explain how excluded participants and unknown outcomes were handled, so the effect of these restrictions cannot be assessed from the record alone.

Second, the primary endpoint is measured at Day 28. Longer-term outcomes are not reported in the registry record. The endpoint is PCR-corrected, but the registry record does not detail the laboratory procedures or classification rules used for correction. That leaves the exact operational process unclear from the posted description.

Third, the study is a three-dose comparison of pyronaridine/artesunate. A placebo or alternative-treatment group is not described. The posted comparisons therefore address differences among dose groups, not comparative effectiveness against other approaches. The registry record also does not report a prespecified clinically important difference or a formal equivalence or non-inferiority margin.

Finally, the registry record does not report the original sample-size justification, the statistical analysis plan, multiplicity procedures, interim analyses, missing-data methods, or detailed results by site or ethnicity. Ethnic differences were an objective to explore, but subgroup results are not reported. These omissions constrain assessment of the design rationale, the robustness of the analyses, and the generalizability of results across the stated regions.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria — NCT01594931.
• Registry record last updated 2021-11-02; status last verified 2021-10.
• Results first posted 2021-09-17.
• 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.

22. Record Summary

The registry record describes NCT01594931, a completed randomized, triple-masked, parallel-group Phase II dose-ranging study of oral pyronaridine/artesunate in adults with acute uncomplicated Plasmodium falciparum malaria. Enrollment was 477; the study started in 2005-07 and reached primary completion in 2006-03. Participants received 6:2 mg/kg, 9:3 mg/kg, or 12:4 mg/kg, with the trial summary describing once-daily dosing for 3 days.

The primary endpoint was PCR-corrected ACPR at Day 28 in a defined efficacy population. Posted response percentages were 95.0%, 99.0%, and 99.0% across the respective dose groups. Recalculated unadjusted risk-difference intervals include zero for both comparisons with the 6:2 mg/kg group. The registry also lists clearance-time and safety outcomes, but does not report the full sponsor analysis plan, multiplicity approach, original sample-size rationale, or missing-data methods.