Daprodustat Bioequivalence and Food Effect Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Daprodustat Bioequivalence and Food Effect Study (NCT03493386), a randomized phase 1 study. The primary outcome is Part 1:Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Last Measurable Concentration (AUC[0-t]) and AUC From Zero Hours Extrapolated to Infinity AUC [0-inf] of Daprodustat.

2. Clinical Question

3. Trial Design

This was a Phase 1, single-centre, open-label, randomized, two-way crossover study of single-dose daprodustat. It had two parts: a bioequivalence comparison of tablet formulations in Part 1, and a food-effect assessment in Part 2. The registry lists 64 participants enrolled overall. Its brief summary describes approximately 52 participants in Part 1 and 12 in Part 2.

In Part 1, participants received both two 2 mg tablets and one 4 mg tablet, with the order randomized. In Part 2, participants received the 4 mg tablet in both fed and fasted conditions, also in randomized order. The group descriptions specify a 5-day washout between periods. This crossover arrangement means each participant serves as their own comparator for the assigned conditions, rather than comparing only separate groups of participants.

The study was open label, so masking was not used. The registry identifies the study as single centre and reports that it started on 2018-04-24, reached primary completion on 2018-06-09, and is completed. GlaxoSmithKline is listed as sponsor. The registry record does not report further details about the centre or the rationale for the planned enrollment.

The primary outcome listed is limited to Part 1 and concerns two AUC measures. The stated blood-sampling schedule extended from pre-dose through 24 hours post-dose. The registry record does not report a numerical comparison of the formulations or a numerical estimate of the food effect. It also does not report a Part 2 primary endpoint under the primary outcome description.

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: Total 64 healthy participants were enrolled in the study which was conducted from 24-April-18 to 09-June-18, study was conducted in two parts, Part 1 was the bioequivalence of daprodustat Tablets and part 2 was food effect on the pharmacokinetics (PK) of daprodustat.

Part 1, Intervention Period 1 (2 Days)

Part 1, Washout Period (at Least 5 Days)

Reasons for not completing this period:

Part 1, Intervention Period 2 (2 Days)

Part 2, Intervention Period 1 (2 Days)

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

6. Primary Endpoint

The registry lists the primary outcome as Part 1:Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Last Measurable Concentration (AUC[0-t]) and AUC From Zero Hours Extrapolated to Infinity AUC [0-inf] of Daprodustat, measured over Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2.

The Part 1 primary endpoint measures daprodustat exposure in blood after dosing. AUC from zero to the last measurable concentration (AUC[0-t]) represents the area under the plasma concentration-time curve up to the final measurable sample. AUC from zero extrapolated to infinity (AUC[0-inf]) extends the exposure measure beyond the last observed concentration using an extrapolation. These are pharmacokinetic measures, not direct measures of clinical benefit.

Blood samples were scheduled before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, and 24 hours post-dose on Day 2. The registry lists the unit as hour*nanogram/milliliter and identifies the summary measure as a geometric mean with geometric coefficient of variation.

In general, AUC is used to summarize overall drug exposure across the measured concentration-time profile. Examining both AUC[0-t] and AUC[0-inf] gives an observed-period measure and an estimate extended to infinity. The registry record does not report the actual geometric means, variability estimates, formulation comparison, or confidence intervals, so the degree of similarity between formulations cannot be evaluated from the endpoint description alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study used a randomized, two-way crossover design. In general, a crossover study assigns participants to receive more than one condition in different periods. Here, Part 1 participants received both tablet presentations, while Part 2 participants received the 4 mg tablet under fed and fasted conditions. Randomizing treatment order helps distribute period order across the sequences. Because each participant contributes measurements under both conditions, comparisons can account for stable differences between participants. That design feature does not remove possible period effects, carryover, or missing measurements; the registry record does not report analyses of those issues.

What does crossover mean for the comparison?

In general, a within-participant comparison focuses on how a participant's outcome differs between periods, rather than treating each period as an unrelated observation. This can make the comparison more informative when participants differ from one another at baseline. It also requires appropriate handling of the paired structure and consideration of whether the earlier treatment could influence the later period. The registry describes a 5-day washout between periods. It does not report the statistical model used for the treatment comparisons, or whether period, sequence, or carryover terms were included.

How were pharmacokinetic outcomes obtained?

The registry says blood samples were collected at prespecified times and that pharmacokinetic parameters were determined by non-compartmental methods using Phoenix WinNonlin version 6.3. In general, non-compartmental analysis derives exposure and related pharmacokinetic measures from concentration-time data without specifying a full compartmental model for how the drug moves through the body. The primary outcomes were AUC[0-t] and AUC[0-inf], reported as geometric means with geometric coefficients of variation. The record does not provide the values obtained from those analyses.

In general, the geometric mean summarizes positive, often skewed measurements on a multiplicative scale. The geometric coefficient of variation describes relative variability on that scale. These summaries are commonly used for pharmacokinetic data, but interpretation of a treatment comparison also requires the comparison estimate and its uncertainty. The registry record does not state the exact comparison procedure, confidence-interval method, or bioequivalence acceptance limits.

Who was included in the pharmacokinetic population?

The endpoint description defines the pharmacokinetic population as participants in the Safety population who received at least one dose and had at least one non-missing pharmacokinetic assessment. The Safety population is described as all randomized participants who received at least one dose. This definition indicates that not every randomized participant necessarily contributed to the pharmacokinetic analysis: a participant also needed at least one usable pharmacokinetic assessment. The number meeting these criteria is not reported in the registry record.

In general, analysis-population definitions matter because results can depend on which participants and measurements are included. The registry gives a population definition but does not report participant flow, exclusions from pharmacokinetic analyses, or how individual missing concentration measurements were handled. It also does not report whether participants were analyzed according to randomized sequence or actual treatment received in any particular analysis.

What does the design not establish?

The registry labels the study randomized and open label. Randomization concerns treatment order; open-label status means masking was not used. Neither label establishes that a particular analysis was unbiased or that its assumptions were met. The record does not report the statistical model, diagnostics, handling of values below quantification limits, or treatment of incomplete concentration-time profiles. Those details could affect interpretation of AUC estimates, but they are not reported in the registry record.

The study's stated aims include bioequivalence and food effect, but the available endpoint description supplies only the Part 1 AUC outcome. A study aim is not a numerical finding. Without the estimates, uncertainty intervals, and analysis details, the planned statistical comparison cannot be reconstructed. No additional statistical procedure should be inferred from the crossover design or from the endpoint labels alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 56 outcome measures and 6 analyses. The primary outcome description includes two AUC measures, while the study has two parts and multiple scheduled sampling times. The record does not reduce the primary outcome to one comparison. The number of analyses and outcomes indicates that several statistical questions were recorded, but the registry information does not specify how the investigators controlled the risk of false-positive findings across them.

In general, multiplicity arises when several outcomes, time points, or comparisons are tested. Without an adjustment, the chance of at least one apparently notable result can increase as the number of tests grows. Whether adjustment is appropriate depends on the analysis goals and hierarchy of outcomes. The statistical plan and any multiplicity procedure are not reported in the registry record. No inference about adjustment should be made from the counts of outcomes or analyses alone.

The primary endpoint description defines the pharmacokinetic population as participants who received at least one dose and had at least one non-missing pharmacokinetic assessment. However, the number included in that population, missing-data handling, exclusions, and participant flow are not reported in the registry record. The record does not state how missing samples or incomplete concentration-time profiles affected AUC calculations.

In general, missing measurements can reduce precision and can affect estimates if the reason for missingness is related to treatment or outcome. The record does not report assumptions about missingness, an imputation method, or sensitivity analyses. It also does not report an interim-analysis plan or a detailed statistical analysis plan. These omissions limit the ability to evaluate the analysis strategy and to distinguish prespecified methods from any later choices.

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 2% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists adverse events by treatment sequence. In Part 1, the sequence receiving two 2 mg tablets followed by one 4 mg tablet had 0 serious adverse events among 51 participants at risk and 3 other adverse events among 51. The reverse sequence had 0 serious adverse events among 52 participants at risk and 1 other adverse event among 52.

For Part 2, the sequence receiving the 4 mg tablet fed followed by fasted had 0 serious adverse events and 0 other adverse events among 12 participants at risk. The sequence receiving the 4 mg tablet fasted followed by fed also had 0 serious adverse events and 0 other adverse events among 12 participants at risk. No deaths are listed in any of the groups.

These are descriptive counts by sequence, not estimates of comparative risk. In general, a count of zero means no event of that type was recorded in that group; it does not establish that the underlying risk is zero. The registry record does not provide further detail about the other adverse events or serious adverse event terms. The groups are small, particularly in Part 2, so the counts alone provide limited information about uncommon events. They should not be interpreted as a complete assessment of safety or as a comparison proving that one condition is safer than another.

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

The registry record describes a controlled pharmacokinetic experiment in healthy Japanese male participants. Its design addresses two distinct questions: whether exposure differs between two tablet presentations in Part 1, and whether food affects exposure after the 4 mg tablet in Part 2. The crossover structure means participants received both conditions within their assigned part, with treatment order randomized.

The primary endpoint is an exposure measure, not a clinical outcome. AUC summarizes plasma concentration over time and is used to characterize pharmacokinetics. The record does not report the numerical AUC findings or a Part 2 food-effect estimate. It therefore does not show how large either comparison was, how precisely it was estimated, or whether a stated bioequivalence criterion was satisfied. A study's stated objective should not be mistaken for its result.

The trial enrolled 64 participants overall and was completed. It was open label and single centre, and the registry identifies the population as healthy Japanese male participants. These features define the context in which the study was conducted; they do not establish how findings would apply to other populations or settings. The registry record does not report enough outcome data to assess that question.

The adverse-event counts describe what was recorded in the listed groups, including no serious adverse events and no deaths. Those observations do not establish absence of risk, especially for uncommon events, and do not replace the pharmacokinetic results. More broadly, this record supports a description of study design, endpoints, and recorded safety counts, but not a conclusion about clinical benefit, treatment effectiveness, or a definitive pharmacokinetic comparison.

13. Why This Trial Matters Statistically

This study illustrates why pharmacokinetic design and reporting need to be considered together. A crossover design can compare conditions within participants, which is useful when the main outcomes are concentration-based measures and the conditions can be administered in separate periods. Randomizing the sequence addresses order assignment, while the washout period is intended to separate treatment periods. The registry describes these design features, but does not report the analysis details needed to evaluate period or carryover effects.

The endpoint also highlights the distinction between defining a measure and reporting a result. AUC[0-t] and AUC[0-inf] specify how exposure was summarized, and geometric means with geometric coefficients of variation describe the planned summaries. Without the actual estimates and their uncertainty, readers cannot judge the magnitude or precision of a formulation comparison. In general, a statistical conclusion depends on both the estimate and the uncertainty around it, not merely on the name of the endpoint or the study's objective.

The two-part structure is another important interpretive feature. Part 1 compares tablet presentations, whereas Part 2 compares fed and fasted conditions. These are different questions, with different participant groups and comparisons. The Part 1 primary outcome description does not provide a corresponding Part 2 endpoint, so the food-effect aim cannot be evaluated from the reported primary endpoint information.

Finally, registry records are most informative when methods, populations, and numerical results are all available. Here, the population definition and sample schedule are described, but analysis population size, missing-data handling, multiplicity procedures, and numerical pharmacokinetic results are not reported in the registry record. Those gaps matter because they constrain reproducibility and prevent a complete assessment of precision and evidential strength.

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 central limitation for interpreting this trial is that numerical pharmacokinetic results are not reported in the registry record. No treatment-specific AUC estimates, comparison estimates, confidence intervals, or statistical test results are available in the record details. The primary objective is therefore described, but the magnitude and precision of its result cannot be assessed.

The endpoint description covers Part 1, while the registry summary also describes a food-effect objective in Part 2. A Part 2 primary endpoint and numerical food-effect results are not reported in the registry record. The stated study aim should not be treated as evidence of a measured or established result.

The registry reports overall enrollment and approximate planned numbers by part, but does not report the final number contributing to each pharmacokinetic analysis. It defines the pharmacokinetic population, yet participant flow, exclusions, and missing-sample handling are not reported in the registry record. This limits assessment of how complete the concentration-time data were.

Additional statistical details are not reported in the registry record, including the comparison model, confidence-interval procedure, bioequivalence limits, multiplicity approach, and sensitivity analyses. The study is single centre, open label, and restricted to healthy Japanese male participants, as described in the record. Those design characteristics define the study context; the record does not establish how its findings would apply beyond that context.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Daprodustat Bioequivalence and Food Effect Study — NCT03493386.
• Registry record last updated 2020-07-08; status last verified 2020-06.
• Results first posted 2019-08-06.
• 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

NCT03493386 is a completed Phase 1, single-centre, open-label, randomized, two-way crossover study sponsored by GlaxoSmithKline. It enrolled 64 healthy Japanese male participants and examined daprodustat tablet bioequivalence in Part 1 and food effect in Part 2.

Part 1 compared a single dose of two 2 mg tablets with a single dose of one 4 mg tablet. Part 2 compared the 4 mg tablet in fed and fasted conditions. The primary outcome listed for Part 1 was AUC[0-t] and AUC[0-inf], with pharmacokinetic analysis by non-compartmental methods.

Numerical pharmacokinetic results, confidence intervals, and a Part 2 primary endpoint are not reported in the registry record. The record lists no serious adverse events or deaths in the treatment sequence groups.