Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy (NCT04487145), a non-randomized phase 4 study. The primary outcome is AUC0-42day in 3-dose Study.

2. Clinical Question

The study is titled “Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy” and is also identified as the DPART Study. Its focus is a drug-drug interaction question: whether piperaquine exposure differs across children taking different ART regimens and children not taking ART. The registry describes an open-label, prospective intensive pharmacokinetic study rather than a randomized treatment comparison.

The primary endpoint population includes five arms in the 3-dose study. The registry specifically excludes C1 and L1 from that endpoint population because those arms were included only in the single-dose study for safety evaluation and their participants were not in the 3-dose study. This distinction matters when reading the posted endpoint displays: the single-dose groups are not part of the stated 3-dose primary endpoint population.

The clinical question is therefore about exposure across defined groups, not a randomized estimate of the causal effect of an ART regimen. Non-random allocation means the groups may differ in age, HIV status, ART use, or other features. The registry record does not report adjustment methods that would address such differences. The results should be read as pharmacokinetic observations in the enrolled groups, with the limitations of this study design.

3. Trial Design

This was a phase 4, non-randomized, open-label, parallel-group study. The registry identifies the study as prospective and intensive in its pharmacokinetic sampling. Enrollment was 194, the status is completed, and the sponsor is the University of California, San Francisco. The study start date is 2020-11-23 and the primary completion date is 2022-04-11.

The seven described arms cover different combinations of HIV status, ART regimen, age range, and sampling schedule. E3 enrolled HIV-infected children age 3 - 10 years on EFV-based ART; L3 enrolled HIV-infected children age 3 - 10 years on LPV/r-based ART; and D3 enrolled HIV-infected children age 11 - 17 years on DTG-based ART. The C3a control group comprised HIV-uninfected children age 3-10 years, while C3b comprised HIV-uninfected children age 11-17 years. These five arms took the 3-dose regimen and form the stated primary endpoint population.

The additional L1 arm comprised HIV-infected children age 3 - 10 years on LPV/r-based ART, and C1 comprised HIV-uninfected children age 3-10 years not on ART. These arms took one oral dose and were included for the single-dose study. The registry says they were not part of the 3-dose study. Across the arm descriptions, children on ART had been receiving that ART for at least 10 days. DP was given orally, with doses based on weight according to 2015 WHO guidelines for DP.

Because allocation was non-randomized and masking was none, participants and investigators were not blinded to group assignment. The parallel structure means the groups are considered alongside one another rather than as successive treatment periods for each participant. However, the registry does not report a random allocation process, a blinded assessment procedure, or an adjusted comparison plan. The listed arm sizes are planning descriptions, not a basis for assuming that every group contributed equally to every analysis. The actual analysis populations and any departures from the planned arm sizes 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.

Before assignment: Single dose study only enrolled 20 children in L1 and 20 in C1 to evaluate the safety in the context of DP and LPV/r drug-drug interaction, only one dose of DP was given in the treatment group (L1). None of those children were included in the 5 groups in the 3-dose full study. So this is not a two-period design.

Only the first 6 of 7 groups are shown.

Single-dose Study for Safety Evaluation

3-dose Study

Analysis population for the primary outcome, as defined in the registry: Only five arms in 3-dose study. because C1 and L1 were only for single-dose study to evaluate safety, and those participants were not in 3-dose study,

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.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as AUC0-42day in 3-dose Study, measured over 42 days.

The primary endpoint is “AUC0-42day in 3-dose Study”: piperaquine AUC from time 0 to 42 days, with units of hr.ug/mL. AUC, or area under the concentration-time curve, summarizes drug concentration over a defined period. It is used in pharmacokinetic studies to represent overall exposure rather than concentration at one isolated sampling time. AUC over the stated interval therefore reflects the pattern of measured piperaquine concentrations during the 42 days following the 3-dose regimen.

The registry specifies a geometric mean as the summary measure and a 95% confidence interval as the dispersion measure. In general, a geometric mean summarizes values on a multiplicative scale and can be suitable when measurements are positive and their distribution is right-skewed. A confidence interval expresses the uncertainty around an estimate under the analysis method; it is not a range that contains every individual participant’s value. Neither the numerical geometric means nor their confidence intervals are reported in the registry record, so the magnitude and precision of the endpoint estimates cannot be described.

The endpoint applies to the five arms in the 3-dose study, not to C1 and L1. Those two groups were in the single-dose study, which the registry says evaluated safety. The endpoint is a measure of piperaquine exposure; it is not itself a clinical outcome or a direct measure of antimalarial effectiveness. AUC can be useful for examining pharmacokinetic differences between groups, but interpretation depends on the measurement schedule, analysis population, and statistical methods. Details beyond the endpoint description are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does AUC summarize?

In general, area under the concentration-time curve (AUC) combines concentration measurements across a specified time interval. It offers a summary of exposure across that interval rather than a comparison at one sampling moment. Here, the endpoint is piperaquine AUC from time 0 to 42 days after the 3-dose study regimen, reported in hr.ug/mL. The phrase “AUC0-42day” identifies the interval in the endpoint title; it does not describe a separate clinical outcome.

Pharmacokinetic interpretation depends on how and when samples were collected and how concentrations were used to estimate the curve. The registry describes the study as intensive pharmacokinetic research, but the sampling schedule, assay details, handling of values below quantification, and AUC estimation method are not reported in the registry record. Those details matter because they determine how raw concentration measurements become an endpoint estimate.

Why report a geometric mean?

In general, a geometric mean is formed on a multiplicative scale and is often used for positive measurements that are skewed rather than symmetrically distributed. It can make a central summary less dominated by a small number of unusually high values than an arithmetic mean, depending on the data distribution. This is a general explanation, not a claim about the distribution in this study. The registry identifies the primary endpoint summary as a geometric mean, but does not report the transformation, model, or other details used to estimate it.

When comparing geometric means, an analysis may express contrasts as ratios, but the registry entries do not specify that a ratio was used. No comparison estimate, standard error, or test result is reported in the registry record. It would therefore be inappropriate to infer the form or significance of an analysis from the endpoint summary alone.

How should a confidence interval be read?

In general, a 95% confidence interval describes uncertainty around an estimated quantity under the assumptions of the method. A narrower interval indicates greater precision for that estimate, while a wider interval indicates more uncertainty. It does not describe the range of values for individual children, and it does not by itself establish a clinically meaningful difference. For a comparison, the interpretation depends on the estimated contrast and its interval, not only on the intervals around separate group summaries.

The registry specifies 95% confidence intervals for the primary endpoint but supplies no numerical interval limits in the registry record. Thus, neither precision nor overlap between groups can be assessed from the endpoint details. Any confidence intervals displayed elsewhere on the page should be read with the population and method used to generate them in view.

What does the study design allow?

This is a non-randomized, open-label, parallel study. In general, randomization can help balance measured and unmeasured participant characteristics across groups, while non-random allocation does not provide that protection. As a result, group differences in a non-randomized study may be associated with features that differ between groups, in addition to the exposure or treatment context of interest. Open-label status means masking is listed as none; the registry does not describe blinded outcome assessment.

The group structure also reflects age and ART categories rather than one common randomized comparison. D3 enrolled children age 11 - 17 years on DTG-based ART, while E3 and L3 enrolled children age 3 - 10 years on EFV-based and LPV/r-based ART, respectively. Their listed HIV-uninfected controls are also separated by age range. These design features are important when interpreting group-level pharmacokinetic summaries. An adjusted model, covariate selection strategy, or causal analysis is not reported in the registry record.

The five-arm primary endpoint population must be kept separate from the single-dose arms. The registry says C1 and L1 were included only in the single-dose study for safety evaluation and were not in the 3-dose study. Combining their participants with the 3-dose groups would not match the stated endpoint population.

What do the planning illustrations show?

The sample-size section contains planning illustrations based on an observed effect, not the trial’s original design. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. For time-to-event tables, the stated quantity is total events; other tables use participants per arm. These are hypothetical planning quantities under assumptions, not observed power and not evidence that the trial was designed to achieve a particular power.

The original sample-size justification, any target power used in the protocol, and the design rationale are not reported in the registry record. The registry entries also do not include the numerical primary endpoint estimates needed to explain the observed effect or assess how the planning scenarios relate to it. Planning illustrations should therefore be separated from the observed study findings and from any claim about the study’s ability to detect a difference.

What statistical details are absent?

The registry reports 0 analyses. A statistical analysis plan, model specification, inferential tests, treatment of repeated or correlated measurements, covariate adjustment, and method for constructing the endpoint confidence intervals are not reported in the registry record. Nor are missing-data procedures, outlier handling, or sensitivity analyses. These omissions limit independent assessment of how the endpoint was analyzed and whether alternative reasonable methods could change the interpretation.

In general, pharmacokinetic data can show skewness and variability, and methods may need to account for the scale and distribution of measurements. That is a general consideration, not evidence that a particular model or correction was used in this study. Over-dispersion, for example, can matter when a count outcome varies more than a simple model expects; the primary endpoint is continuous AUC, and no modeling details are reported to establish whether over-dispersion or another distributional issue was assessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 14 outcome measures and 0 analyses. It identifies a primary piperaquine AUC endpoint for the five-arm 3-dose study, but the statistical analysis plan and any strategy for handling multiple outcomes or comparisons are not reported in the registry record. There is no reported hierarchy of secondary endpoints, family-wise error approach, false discovery approach, or indication of which group contrasts were confirmatory. Without those details, the extent to which the displayed comparisons account for multiplicity cannot be assessed.

Multiplicity is a general concern when several outcomes, groups, or contrasts are examined: the chance of at least one apparently unusual result can rise as the number of analyses increases. This general point does not mean that any particular finding in this study is false. It means that interpretation of separate estimates and tests benefits from knowing which comparisons were planned in advance and how the analysis treated them. That information is not reported in the registry record.

Missing-data handling is also not reported in the registry record. The listed enrollment is 194, but the number included in each endpoint analysis, participant flow, reasons for missing pharmacokinetic measurements, and any imputation or complete-case approach are not stated in the registry record. The analysis populations for safety outcomes are also not described beyond the group-level counts and denominators shown in the registry.

In general, missingness can affect an estimate if participants with available measurements differ from those without them. Whether that concern applies depends on the amount, timing, and reason for missing data, none of which is reported in the registry record. The non-randomized group structure adds a separate interpretive limitation: statistical adjustment and population definitions would be needed to understand whether comparisons account for group differences, but these methods are not reported. Consequently, uncertainty about multiplicity and missingness should accompany any reading of group comparisons, rather than being treated as evidence that a particular direction or magnitude of bias occurred.

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 reports serious adverse events by study group. The serious-event count is 0 in E3, D3, L3, C3a, C3b, C1, and L1; deaths are also listed as 0 in every group. These are counts as recorded in the registry, not proof that no serious event could have occurred outside the recorded observation or reporting process. The registry entries do not provide event definitions, observation duration, ascertainment procedures, or attribution to DP.

Other adverse events are listed separately. The reported affected counts are 1 for E3, 0 for D3, 8 for L3, 2 for C3a, 0 for C3b, 0 for C1, and 0 for L1. These counts should be interpreted alongside the listed group denominators in the adverse-event display. They are descriptive counts, not adjusted comparisons or rates derived. No event terms are posted in the summarized record details, so the nature or clinical importance of these events cannot be characterized.

Group counts alone do not establish causation. The study is non-randomized, and the registry does not report whether events were judged related to DP or ART, how events were collected, or whether severity grading was used beyond the serious-event category. The counts also should not be read as a comparison of underlying risks without additional methods and context. They describe what the registry reports, not a conclusion about safety for an individual child.

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

The registry describes a completed, open-label, non-randomized pharmacokinetic study of DP in children across ART and HIV-status groups. It specifies a primary outcome—piperaquine AUC from time 0 to 42 days in the 3-dose study—and identifies a geometric mean with a 95% confidence interval as the planned summary. The registry entries also report group-specific adverse-event counts, including no recorded serious adverse events and no deaths in the listed groups.

These registry entries do not establish the size or direction of any difference in piperaquine exposure. Numerical primary endpoint estimates and confidence intervals are not reported in the registry record. Without those values, the precision and pattern of group results cannot be described. The registry also lists 0 analyses and does not report the statistical model, adjustment approach, multiplicity strategy, missing-data procedures, or analysis populations. These absences make it impossible to assess the detailed inferential analysis from the registry entries alone.

The study’s non-randomized design means any group differences should not automatically be interpreted as effects caused by a particular ART regimen. Group membership is associated with distinctions in HIV status, ART use, and age range. The registry’s control groups are designated for specific arms, but they are not randomized controls. The data can describe the enrolled groups and their measured pharmacokinetic outcomes; they cannot, on the information, isolate an ART regimen’s causal effect from other differences.

The primary endpoint is pharmacokinetic rather than a clinical malaria outcome. All children were malaria-uninfected at enrollment, and the endpoint concerns piperaquine exposure. It does not directly demonstrate prevention or treatment of malaria, nor does it establish a clinical benefit or harm. Likewise, the adverse-event counts are descriptive and do not establish event causation.

The planning illustrations on the page are not observed power and do not substitute for the original sample-size justification, which is not reported in the registry record. They should be understood as hypothetical calculations under stated assumptions. The main defensible reading is therefore limited: the record describes the study structure and certain reported counts, while the numerical primary result and analytical context needed for stronger statistical conclusions are not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically interesting because it frames a pharmacokinetic question across several clinically distinct groups while using a non-randomized design. The contrast is not simply between two exchangeable arms: the registry separates children by HIV status, ART regimen, age range, and whether they received a single dose or the 3-dose regimen. Recognizing those distinctions is essential before interpreting group summaries or comparing displayed estimates.

The endpoint also illustrates the difference between a pharmacokinetic summary and a clinical outcome. AUC summarizes piperaquine exposure across the specified interval, while the study’s primary endpoint is not a direct measure of malaria infection or another clinical event. Statistical interpretation must match the endpoint actually measured and avoid extending an exposure estimate into a clinical claim not supported by the record.

The study highlights how much an estimate’s interpretation depends on reporting. A geometric mean and confidence interval are specified, but numerical values, analysis methods, and analysis populations are not reported in the registry record. Knowing the estimate and its uncertainty would be necessary to describe the observed pattern and its precision; knowing the model and population would help assess how it was obtained. In their absence, the design and endpoint can be explained, but the primary result cannot be quantified from these registry entries.

Finally, this record illustrates why safety counts and planning illustrations need careful framing. The adverse-event counts are descriptive, not causal comparisons. The sample-size calculations are planning illustrations based on assumptions, not observed power or a reconstruction of the trial’s original design. Separating observed data, design features, and hypothetical calculations keeps the statistical account aligned with what the registry actually reports.

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.

Several limitations specific to this study affect interpretation. First, allocation is non-randomized and masking is none. Differences between groups may reflect their composition as well as ART context, and the registry does not report an adjusted analysis intended to account for such differences. The groups also do not share identical age ranges: D3 and C3b cover children age 11-17 years, while E3, L3, and C3a cover children age 3-10 years. Direct comparisons across these categories therefore require particular care.

Second, the primary endpoint is limited to the five arms in the 3-dose study. C1 and L1 were included in the single-dose study for safety evaluation, and their participants were not in the 3-dose study. Results from those arms should not be treated as part of the primary AUC population. The study includes 194 participants overall, but the analyzed population for each endpoint and the participant flow are not reported in the registry record.

Third, the numerical primary endpoint results are not reported in the registry record. Although the endpoint type, unit, summary measure, and confidence-interval level are specified, the estimates and intervals needed to assess magnitude and precision are absent in the registry record. The registry also lists 0 analyses, and does not report the statistical model, sampling and assay details, missing-data methods, or multiplicity procedures.

Finally, the safety information is limited to group counts. Event descriptions, attribution, collection methods, and observation duration are not reported in the registry record. The adverse-event counts therefore cannot establish causation or support a detailed assessment of event patterns. These limitations do not invalidate the registry’s descriptive information, but they constrain the conclusions that can be drawn from it.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy — NCT04487145.
• Registry record last updated 2025-03-14; status last verified 2025-02.
• Results first posted 2025-03-14.
• 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 DPART Study (NCT04487145), titled “Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy,” is a completed phase 4, non-randomized, open-label, parallel study sponsored by the University of California, San Francisco. The registry reports enrollment of 194. The study start date is 2020-11-23, and the primary completion date is 2022-04-11.

The study examined DP in HIV-infected children receiving EFV-, LPV/r-, or DTG-based ART and HIV-uninfected children not on ART. The primary outcome is piperaquine AUC from time 0 to 42 days in the 3-dose study, summarized as a geometric mean with a 95% confidence interval. C1 and L1 were single-dose arms and are excluded from that endpoint population.

The registry record reports group-level serious and other adverse-event counts but does not report numerical primary endpoint estimates, statistical analyses, or detailed analysis methods. The design is non-randomized, so group comparisons are descriptive unless supported by methods and assumptions not reported in the registry record.