This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects (NCT03258762), a non-randomized phase 1 study. The primary outcome is Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03258762 |
| Phase | Phase 1 |
| Condition | Toxoplasmosis |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 14 |
| Arms in the primary outcome | n/a |
| Lead sponsor | GlaxoSmithKline |
| Results posted | Yes |
2. Clinical Question
Population
Healthy Japanese and Caucasian male subjects. The registry lists Toxoplasmosis as a condition, but the participants described in the study arms were healthy volunteers, not patients being treated for toxoplasmosis. The recorded enrollment is 14.
Intervention
A single oral dose of pyrimethamine 50 mg, given with calcium folinate 15 mg on Day 1 after an overnight fast of at least 10 hours. Calcium folinate was then administered once daily until Day 8.
Comparator
The study describes parallel groups of Japanese and Caucasian subjects, not a randomized treatment-control comparison. Allocation was non-randomized, and the groups should not be interpreted as like-for-like control arms.
Primary question
The primary endpoint was the maximum observed concentration, or Cmax, of pyrimethamine in healthy Japanese male participants. The record describes pharmacokinetic sampling and calculation, but does not report the Cmax result. It therefore does not establish from the posted results how the measured concentrations compared between the population groups.
The registry describes a Phase I, single-centre, open-label study intended to evaluate pharmacokinetics, safety and tolerability. Its background notes that pyrimethamine had not been approved by the Japanese regulatory body and that confirmation of its pharmacokinetics in Japanese and Caucasian healthy subjects had been requested. That stated regulatory context explains the population focus, but is not itself evidence of a pharmacokinetic difference.
The main question is descriptive: what pyrimethamine concentrations and pharmacokinetic parameters were observed after the stated dose in these healthy male participants? The record names a primary Cmax outcome for the Japanese participants and secondary pharmacokinetic outcomes for Caucasian participants. It does not provide numerical endpoint results or a formal statistical comparison between groups. Any interpretation of a population difference must therefore be limited by the absence of those reported results and by the non-randomized design.
3. Trial Design
This was a Phase I, completed, single-centre study with an open-label, parallel-group design. Allocation was non-randomized and masking was absent. The registry lists enrollment of 14. The two arm descriptions identify healthy Japanese male subjects and healthy Caucasian male subjects. Because the groups were not assigned at random, they are population groups rather than randomized treatment and control arms.
Participants were scheduled to receive a single oral dose of pyrimethamine 50 mg with calcium folinate 15 mg on Day 1, in the fasted state after an overnight fast of at least 10 hours. Calcium folinate was administered once daily until Day 8. Blood sampling for pharmacokinetic analysis and safety assessments was planned before dosing and over 22 days after dosing. The primary outcome timeframe specifies pre-dose and 1, 2, 4, 6, and 12 hours post-dose on Day 1, followed by Day 2, Day 3, Day 4, Day 6, Day 8, Day 15, and Day 22.
The record says screening was to occur within 30 days before the first dose and that each subject would participate for approximately 2 months from screening to follow-up. The study start is recorded as 2017-09-25 and primary completion as 2017-11-19. The status is COMPLETED.
The study was designed to characterize pharmacokinetics and assess safety and tolerability after the described dosing regimen, rather than to test a randomized treatment contrast. Open-label status means masking was not used; for pharmacokinetic concentration measurements, the measured laboratory values are distinct from subjective assessments, though the registry does not report laboratory procedures. The record does not report a detailed protocol, a sample-size justification, or a statistical analysis plan. These omissions limit assessment of how design decisions were selected and how the planned analyses were to be conducted.
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: A total of 14 healthy participants were enrolled in this study.
Overall Study
| Stage | Healthy Japanese Participants | Healthy Caucasian Participants |
|---|---|---|
| STARTED | 7 | 7 |
| COMPLETED | 7 | 6 |
| NOT COMPLETED | 0 | 1 |
Reasons for not completing this period:
| Reason | Healthy Japanese Participants | Healthy Caucasian Participants |
|---|---|---|
| Lost to Follow-up | 0 | 1 |
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.
| Characteristic | Unit | Healthy Japanese Participants | Healthy Caucasian Participants | Total |
|---|---|---|---|---|
| Participants analysed | 7 | 7 | 14 | |
| Age, Continuous | Years | 29.0 (SD 3.27) | 30.7 (SD 6.02) | 29.9 (SD 4.74) |
| Sex: Female, Male: Female | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Male | Participants | 7 | 7 | 14 |
| Race/Ethnicity, Customized: Asian: Japanese Heritage/East Asian | Participants | 7 | 0 | 7 |
| Race/Ethnicity, Customized: White/Caucasian/European heritage | Participants | 0 | 7 | 7 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants, measured over Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | Nanogram per milliliter |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the maximum observed concentration, or Cmax, of pyrimethamine in healthy Japanese male participants. Cmax is the highest concentration measured among the sampled time points after dosing. It is used in pharmacokinetic studies to describe the observed peak concentration, complementing measures that characterize exposure over time. It does not, by itself, describe the entire concentration-time profile or how long the drug remains in the body.
The registry identifies the unit as nanogram per milliliter and the summary measure as a geometric mean with geometric coefficient of variation as the dispersion measure. Blood samples were collected at the listed pre-dose and post-dose time points, and pharmacokinetic parameters were calculated using non-compartmental analysis. The population definition for this endpoint is the Pharmacokinetic Population: participants who received at least one dose of study treatment and had a pharmacokinetic sample taken and analyzed.
The endpoint description explains what was to be measured, not what value was observed. The Cmax estimate and its dispersion are not reported in the registry record. No confidence interval or inferential comparison for this primary endpoint is reported either. As a result, the record supports describing the endpoint and its measurement schedule, but not quantifying the peak concentration or judging its precision from posted numerical results.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the study objective, population, dosing regimen and primary pharmacokinetic measure. It does not report the numerical Cmax result for the Japanese participants. It also does not report numerical results for the secondary pharmacokinetic outcomes. Consequently, the posted information does not permit a reader to describe the magnitude or variability of the measured concentrations, or to assess whether the results were precise enough for a particular conclusion.
The intended primary summary is a geometric mean, accompanied by a geometric coefficient of variation. In general, a geometric mean summarizes measurements on a multiplicative scale and can be useful for concentrations that are positively skewed. A geometric coefficient of variation describes relative dispersion on that scale. These are general interpretations of the stated summaries; the actual estimate and dispersion are not reported in the registry record.
The comparison between Japanese and Caucasian participants is not a randomized comparison. The study used non-randomized parallel groups, so differences between their results, if reported, could not automatically be attributed to population group alone. In general, non-randomized group comparisons may reflect other characteristics that differ between groups, as well as the factor of interest. The registry itself flags that the arms are not a like-for-like control comparison. No adjusted analysis or formal test comparing the groups is reported.
The record lists the primary endpoint in Japanese male participants and secondary pharmacokinetic outcomes in Caucasian male participants. The named secondary measures include Cmax, AUC (0-t), AUC (0-inf), AUC (0-24), Tmax, T1/2, CL/F, and Vd/F. These outcomes represent different aspects of concentration, exposure, timing, elimination and apparent disposition. Their presence in the outcome list does not indicate that their values or comparisons are available: numerical results are not reported in the registry record.
The registry reports 36 outcome measures and zero analyses. That distinction matters: listed outcomes describe what was measured or intended for reporting, while analyses would document statistical results or comparisons. Neither count supplies the missing endpoint estimates. Although the record includes planning assumptions for sample-size illustrations based on an observed effect, it does not give the underlying effect or the numerical planning outputs in the registry record for this analysis. Such illustrations are planning exercises, not observed power and not evidence about the study's findings.
The safety record gives serious adverse event counts and other adverse event counts for each group, as well as deaths. These are descriptive counts, not comparative evidence about treatment effects. With the study's small listed groups and the absence of a randomized control arm, safety counts should be read as what was recorded in this study rather than as a reliable estimate of comparative risk. The registry does not report detailed event terms for serious adverse events.
Overall, the posted record is informative about the study's design and intended pharmacokinetic characterization, but not about the numerical primary result. Neither a conclusion about a difference between groups nor a conclusion about precision can be drawn from endpoint values that are not reported. The background rationale and completed status do not substitute for outcome estimates.
9. Statistical Methods Explained
The registry describes pharmacokinetic parameters calculated by non-compartmental analysis. In general, non-compartmental methods summarize the observed concentration-time data without requiring the researcher to specify a detailed compartment model. The accuracy of derived parameters depends on the sampling schedule, the measured concentrations and the methods used to handle the terminal portion of the concentration profile. The record gives the planned sampling times but does not report those measured concentrations, detailed calculation procedures, or results.
What does Cmax represent?
Cmax is the largest measured concentration among the samples taken after dosing. It is an observed peak, so its value can depend on when samples are collected relative to the actual concentration peak. The registry lists samples at pre-dose and 1, 2, 4, 6, and 12 hours post-dose on Day 1, along with subsequent sampling on Day 2, Day 3, Day 4, Day 6, Day 8, Day 15, and Day 22. The record does not report the observed Cmax, the time at which it occurred, or the underlying concentration data.
Why use a geometric mean?
In general, pharmacokinetic measurements are often summarized on a logarithmic scale when values are positive and variability is better understood proportionally than additively. The geometric mean corresponds to averaging after logarithmic transformation and converting back to the original scale. It describes a central value in multiplicative terms. The registry specifies a geometric mean for the primary Cmax outcome, but does not report its numerical value.
The stated dispersion measure is the geometric coefficient of variation. In general, this describes the spread of measurements relative to their geometric mean, rather than expressing spread in the original measurement units as a standard deviation would. It can help readers understand how variable individual measurements are around a geometric summary. The registry gives no numerical geometric coefficient of variation for the primary endpoint, so the observed variability cannot be assessed.
How do the other pharmacokinetic measures differ?
The secondary outcomes named for healthy Caucasian male participants include Cmax and several area-under-the-curve measures: AUC (0-t), AUC (0-inf), and AUC (0-24). In general, an area-under-the-curve measure summarizes concentration over a defined time span or an extrapolated interval, and is used to describe exposure rather than only the peak. Tmax is the time associated with the maximum observed concentration. T1/2 describes a half-life parameter, while CL/F and Vd/F are apparent clearance and apparent volume of distribution measures when oral bioavailability is not separately known. These definitions explain the general roles of the outcome names; no numerical values for these secondary outcomes are reported in the registry record.
What can a confidence interval tell a reader?
In general, a confidence interval expresses the uncertainty of an estimate under a specified statistical procedure. A narrower interval indicates greater precision under that procedure, while a wider interval indicates less precision. It is not a range containing a fixed proportion of individual participant values, and it does not establish clinical importance by itself. The registry does not report a confidence interval for the primary endpoint, nor does it provide enough numerical outcome information to reconstruct one from the stated record.
What do the sample-size illustrations mean?
The sample-size assumptions describe planning illustrations computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrated effect is a stated fraction of the observed effect. In general, such calculations ask how many participants per arm might be needed under specified assumptions to detect a chosen effect at a chosen power. They are not a measure of the power actually achieved in the completed study. The sample-size assumptions also say that time-to-event examples use total events, while other examples use participants per arm. No numerical planning outputs or underlying observed effect are reported in this record, so no particular sample-size result can be interpreted.
These planning calculations are especially limited as a guide to this study because the actual study was a non-randomized pharmacokinetic characterization, not a randomized comparison with equal allocation. The planning assumptions are illustrative and should not be mistaken for the study's original design rationale. The registry does not report the study's own sample-size justification, or whether the planning illustration corresponds to a prespecified comparison.
Why does over-dispersion matter in general?
Over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model understates variability, its standard errors may be too small and intervals or tests may appear more certain than warranted. A suitable model or variance estimate should reflect the structure of the data. This is a general statistical consideration, not a reported feature of this study; the registry does not describe an inferential model or report whether over-dispersion was assessed.
The registry's primary endpoint description defines the Pharmacokinetic Population as participants who received at least one dose and had a pharmacokinetic sample taken and analyzed. This is an analysis-population definition, not a report of how many participants met it. The actual analysis population size and any exclusions are not reported in the registry record. Without the estimates, variability measures, analysis-population details and inferential methods, readers can identify the intended statistical summaries but cannot independently evaluate their precision or reproduce the analyses.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 36 outcome measures, including the primary Cmax outcome in healthy Japanese male participants and secondary pharmacokinetic outcomes in healthy Caucasian male participants. It reports zero analyses. The outcome list therefore documents the measures named in the record, but does not provide a corresponding set of numerical results or inferential comparisons.
When a study evaluates many outcomes or performs many statistical tests, the chance of at least one apparently notable result can increase. General approaches to multiplicity include prespecifying a primary outcome, adjusting significance thresholds, or interpreting secondary results as exploratory. The registry does not report whether multiplicity adjustments were planned or used, or how the primary and secondary outcomes were handled statistically beyond their stated labels.
Missing-data handling is not reported in the registry record. The primary endpoint description defines the Pharmacokinetic Population as participants who received at least one dose and had a pharmacokinetic sample taken and analyzed, but it does not describe how missing samples, incomplete concentration profiles, or unavailable endpoint values were handled. The record also does not give the number included in the pharmacokinetic analysis population.
The record does not report an analysis plan, imputation methods, sensitivity analyses, or reasons for missing measurements. These details matter because missing samples can affect observed peak concentrations and derived pharmacokinetic parameters. No assumption about how missing data were treated should be made from the population definition alone.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Healthy Japanese Participants | 0 | 7 | 0.0% |
| Healthy Caucasian Participants | 0 | 7 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Healthy Japanese Participants | 0 of 7 |
| Healthy Caucasian Participants | 0 of 7 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Healthy Japanese Participants | 2 of 7 |
| Healthy Caucasian Participants | 6 of 7 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Healthy Japanese Participants | Healthy Caucasian Participants |
|---|---|---|---|
| Folliculitis | Infections and infestations | 0 of 7 | 1 of 7 |
| Upper respiratory tract infection | Infections and infestations | 0 of 7 | 1 of 7 |
| Viral infection | Infections and infestations | 1 of 7 | 0 of 7 |
| Abdominal discomfort | Gastrointestinal disorders | 0 of 7 | 1 of 7 |
| Nausea | Gastrointestinal disorders | 0 of 7 | 1 of 7 |
| Headache | Nervous system disorders | 0 of 7 | 1 of 7 |
| Tension headache | Nervous system disorders | 1 of 7 | 0 of 7 |
| Catheter site pain | General disorders | 0 of 7 | 1 of 7 |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | 0 of 7 | 1 of 7 |
| Dry skin | Skin and subcutaneous tissue disorders | 1 of 7 | 0 of 7 |
The registry reports serious adverse events for Healthy Japanese Participants and Healthy Caucasian Participants. Each group lists 7 at risk, with 0 serious adverse events and 0 deaths. For other adverse events, the Japanese group lists 2 affected participants and the Caucasian group lists 6 affected participants; each group lists 7 at risk.
These are descriptive counts for the groups in this study. Serious adverse events and other adverse events are separate categories in the record, so zero serious events does not mean that no adverse events of any kind were recorded. The registry lists no top serious adverse event terms. It does not report a detailed description of the other events in the registry record for interpretation.
Counts do not establish that the study treatment caused an event, and the figures should not be read as a randomized safety comparison. The groups were non-randomized population groups, not like-for-like control arms. The record also does not provide a statistical comparison or additional detail about event severity, timing, or attribution. These figures describe what the registry reports, not comparative risk or a complete assessment of safety.
12. What the Result Does, and Does Not, Mean
The record shows that a completed Phase I study was designed to examine pyrimethamine pharmacokinetics, safety and tolerability in healthy Japanese and Caucasian male subjects. It specifies a single oral pyrimethamine dose with calcium folinate, the planned sampling schedule, the primary Cmax outcome, and a Pharmacokinetic Population definition. It also records adverse event counts by group.
What the record does not show is the numerical primary endpoint result. The Cmax geometric mean and geometric coefficient of variation are not reported. The listed secondary outcomes also have no numerical results in the record. As a result, the posted information does not reveal the concentration levels, the variability of those levels, the size of any difference between groups, or the precision of an estimate.
The design does not support treating Japanese and Caucasian participants as randomized treatment and control groups. Any observed contrast, were it available, would be descriptive unless supported by an appropriate analysis and interpretation. Non-randomized groups may differ in ways other than the population characteristic under study; the registry does not report an adjusted comparison that addresses this issue.
The safety counts show no serious adverse events or deaths listed in either group, and other adverse events were recorded in both. Those counts are limited descriptive observations and do not establish causality or comparative safety. The study's completed status does not fill gaps in reporting, and the background rationale does not establish the findings.
In general, a pharmacokinetic study can characterize concentration and exposure patterns in the population studied. Whether its results generalize to patients, other populations, other dosing regimens, or clinical outcomes requires evidence beyond the stated design and outcome definitions. The registry record does not report clinical efficacy outcomes, and the described healthy-subject study should not be read as a test of treatment benefit for toxoplasmosis.
13. Why This Trial Matters Statistically
This study is statistically useful to examine as an example of a descriptive pharmacokinetic design distinct from a randomized efficacy trial. Its central outcome is a concentration measure, and its stated analysis uses a geometric mean and geometric coefficient of variation. Reading those measures correctly requires distinguishing a peak concentration from exposure over time and separating a central summary from a measure of variability.
The design also highlights why group comparisons need context. Japanese and Caucasian participants were enrolled in non-randomized parallel groups, with no masking. The registry explicitly notes that the arms are not a like-for-like control comparison. Statistical contrasts between such groups, if reported, would need to be interpreted with attention to possible differences other than group membership; a simple numerical contrast would not by itself identify a causal effect.
The record's endpoint definitions and detailed sampling schedule describe what investigators intended to measure, while its outcome reporting does not include numerical estimates. This distinction is important in statistical reading: a named endpoint is not a result, and a planned population definition is not a reported analysis population size. The record lists 36 outcome measures and zero analyses, making the gap between listed outcomes and posted statistical findings especially clear.
The sample-size assumptions offer another general lesson. Planning calculations depend on chosen assumptions and an effect size, and they should not be treated as observed power after a study is complete. Here, the illustrations are described as based on an observed effect and specified assumptions, but the numerical planning outputs and the underlying effect are not reported in the record available for this analysis.
Finally, adverse-event counts are not a substitute for a comparative safety model. They are descriptive, and the non-randomized population groups do not provide a randomized control comparison. Careful interpretation separates what the registry documents from what statistical methods might ordinarily be used to investigate, but which are not reported for this study.
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 principal limitation for statistical interpretation is that the registry record does not report numerical results for the primary Cmax endpoint. Although it identifies the summary measure, dispersion measure, unit, timeframe and analysis population definition, it gives no estimate or uncertainty measure. The secondary pharmacokinetic results are also not reported numerically. The planned measures therefore cannot be used to assess the observed concentration profile or compare groups.
The non-randomized, open-label, parallel-group design does not create a randomized control comparison. The two groups differ by the population characteristic of interest, but the record does not describe adjustment for other characteristics or report a formal comparison. Any group contrast would be descriptive and potentially affected by differences not accounted for in the registry record.
The registry does not report the pharmacokinetic analysis population size, missing-data handling, detailed statistical analysis plan, sample-size justification, or multiplicity procedures. Although it defines the Pharmacokinetic Population and lists planning assumptions for sample-size illustrations, those details do not establish the analysis actually conducted or how incomplete data were treated. The numerical planning outputs and the observed effect used for the illustration are not reported.
The safety information is limited to counts by group, with no serious adverse event terms listed and no further details about other adverse events in the registry record. These counts cannot establish causality or comparative risk. The study was conducted in healthy male participants, so its described population also limits what can be inferred about patients with toxoplasmosis or other populations. The registry does not report clinical efficacy outcomes.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects — NCT03258762.
- Registry record last updated 2020-03-27; status last verified 2020-03.
- Results first posted 2019-03-27.
- 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.
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18. Record Summary
NCT03258762 is a completed Phase I, single-centre, open-label, non-randomized, parallel-group study of pyrimethamine in healthy Japanese and Caucasian male subjects. Recorded enrollment is 14. The study describes a single oral pyrimethamine dose of 50 mg with calcium folinate 15 mg on Day 1, followed by daily calcium folinate through Day 8.
The primary endpoint is Cmax of pyrimethamine in healthy Japanese male participants, summarized as a geometric mean with geometric coefficient of variation. Pharmacokinetic parameters were to be calculated by non-compartmental analysis. The registry lists 36 outcome measures and zero analyses, but does not report numerical primary or secondary pharmacokinetic results. Safety counts list no serious adverse events or deaths in either group, with other adverse events recorded in both. Because allocation was non-randomized, the groups are not like-for-like control arms.