Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects (NCT03874234), a randomized phase 1 study. The primary outcome is Part A- Cohorts 1 and 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and SAEs.

2. Clinical Question

The trial was designed to characterize safety, tolerability and pharmacokinetics rather than to test a clinical treatment effect in a patient population. Its registered condition was Leishmaniasis, but participants were healthy subjects. The key statistical question for the posted primary outcome is descriptive: how many participants in the reported treatment groups experienced non-serious or serious adverse events during follow-up? The registry record does not give a single treatment-effect estimate or a formal statistical comparison for this outcome.

The study's sequential structure matters to interpretation. Part B was contingent on review of safety, tolerability and pharmacokinetic data from Part A, and the registry record reports no participants at risk for the listed Part B groups. Thus, the available safety counts concern Part A, Cohorts 1 and 2, rather than a complete comparison across all planned study components.

3. Trial Design

This was a randomized, double-blind, placebo-controlled, Phase 1 study with a sequential model. The official title describes sponsor unblinding. The stated purpose was to assess safety, tolerability and pharmacokinetics after single and repeat doses of GSK3186899 in healthy participants, and to investigate the effect of food on pharmacokinetics. The study is listed as terminated. The registry record gives a start date of 2019-04-30 and a primary completion date of 2019-10-17.

Part A was the single-ascending-dose phase. Cohorts 1 and 2 used a four-way crossover design under fasted conditions, with GSK3186899 and placebo administered in a 3:1 ratio in each treatment period. Cohort 1 included the 30 mg, 60 mg and 120 mg doses, alongside placebo. Cohort 2 included the 300 mg, 600 mg and 800 mg doses, alongside placebo. The registry record says dose level 7 was not conducted because dose escalation stopped at dose level 6 (800 mg). The available primary safety data combine the placebo and 300 mg arms across Cohorts 1 and 2 because their dosing strategies were described as similar under the protocol.

Cohort 3 was a two-way crossover intended to compare fasted and fed administration of GSK3186899. Part B was planned as a repeat-dose escalation phase, with participants randomized to GSK3186899 or placebo under fed or fasted conditions. The planned regimen was twice daily on Days 1 to 10. The registry record states that Part B would proceed based on review of Part A safety, tolerability and pharmacokinetic data.

Enrollment was 25. That figure is not interchangeable with the treatment-specific at-risk counts: this was a sequential crossover study, and the primary safety population was defined by treatment received. The registry record does not report the rationale for the enrollment target or a detailed account of how participants progressed through each planned study component.

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 25 participants were enrolled (Enrolled Population consisted of all participants who passed screening and entered the study) in this study (Part A: Cohort 1- 11 participants, Cohort 2- 14 participants). Dose level 7 was not conducted as dose escalation was stopped at dose level 6 (800 mg), as the stopping criteria was reached with the 800mg dose and no further dose escalation was recommended.

Only the first 6 of 13 groups are shown.

Part A: Cohort 1-Period 1 (Day1)

Reasons for not completing this period:

PartA:Cohort1-WashoutPeriod1(Upto Day10)

Part A: Cohort 1-Period 2 (Day1)

Reasons for not completing this period:

PartA:Cohort1-WashoutPeriod2(Upto Day10)

Analysis population for the primary outcome, as defined in the registry: Safety Population. Data for Part A: Cohorts 1 and 2- Placebo and Part A: Cohorts 1 and 2- GSK3186899 300 mg arms were presented in a single arm because of similar dosing strategies as pre-defined in the protocol. Dose level 7 was not conducted as dose escalation was stopped at dose level 6 (800 mg), as the stopping criteria was reached with the 800mg dose and no further dose escalation was recommended.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: This study was terminated after completion of Cohort 2, Period 3 of Part A following strategic review after emergence of nonclinical data with non-GlaxoSmithKline asset. Hence, no participants were enrolled in Cohort 2 Period 4 and Cohort 3 of Part A and in all Cohorts of Part B. Dose level 7 was not conducted as dose escalation was stopped at dose level 6 (800 mg), as the stopping criteria was reached with the 800mg dose and no further dose escalation was recommended.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part A- Cohorts 1 and 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and SAEs, measured over Up to Week 12.

The primary endpoint is the number of participants with non-serious adverse events and serious adverse events in Part A, Cohorts 1 and 2, through Week 12. An adverse event is defined in the registry record as an untoward medical occurrence temporally associated with study treatment, whether or not considered related to treatment. A serious adverse event includes events meeting the specified seriousness criteria, such as death, life-threatening events, inpatient hospitalization or its prolongation, persistent disability or incapacity, congenital anomaly or birth defect, or important medical events that may require intervention to prevent such outcomes.

Counting participants with events is a descriptive safety measure. It gives a direct account of how many people in a treatment group had at least one event meeting the relevant category, rather than describing event severity in a continuous scale or estimating a pharmacokinetic quantity. The registry presents non-serious and serious event counts separately, alongside the number at risk in each listed group. These counts are useful for characterizing the safety experience recorded for the studied doses, but they do not by themselves establish whether an event was caused by treatment. The adverse-event definition expressly includes events regardless of whether they were considered treatment-related.

The stated Safety Population consisted of randomized participants who received at least one dose of study treatment. The primary outcome's reported population is limited to Part A, Cohorts 1 and 2. The registry record does not report a formal treatment-comparison analysis for this endpoint, and the primary outcome has several categories or time points rather than a single reduced comparison. The endpoint should therefore be read as a set of descriptive counts, not as a standalone estimate of comparative risk.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a count of participants with an event represent?

For a binary safety outcome, each participant is classified according to whether the specified event category occurred during the relevant observation period. The registry endpoint is the number of participants with non-serious adverse events and serious adverse events, reported separately for each treatment group. The associated at-risk count identifies the group denominator for those counts. This is a descriptive summary, not a model-based estimate of a treatment effect.

A participant count is different from an event count. The endpoint title specifies participants with events; a participant who experiences more than one event in a category is not necessarily represented as multiple participants in that category. The registry record does not provide event-level detail in the listed primary outcome details, so the number, timing, duration and clinical characteristics of individual events are not available for interpretation.

Why does the design affect comparisons?

A parallel-group trial typically assigns participants to different groups and follows each group under its assigned treatment. A crossover design instead exposes participants to different conditions over treatment periods. Comparisons in a crossover study can be affected by within-participant correlation, period effects, order effects and carryover. A washout period can be intended to reduce carryover, but the statistical analysis still needs to account for the design. The registry record describes crossover periods for Part A, including at least 10 days of washout between periods for Cohort 2 and Cohort 3, but does not report the primary endpoint analysis method or how crossover features were handled.

The study was also sequential: Part B was to be initiated following review of Part A data. Such a structure can affect which participants and outcomes are observed in later components. The registry record does not report whether Part B was initiated, why the overall study was terminated, or how the sequential decision process was analyzed. Its listed Part B safety groups have 0 participants at risk in the reported data.

Why might raw counts be more informative than an unsupported comparison?

Raw counts preserve what the registry reports without imposing a statistical model or creating an unreported estimate. Here, the primary endpoint encompasses multiple treatment groups and event categories, and the registry entries state that the outcome was not reduced to a single comparison. No inferential analyses are listed. Therefore, presenting a single effect estimate or significance test as though it were the trial's analysis would be misleading.

In general, a confidence interval communicates uncertainty around an estimate. For a binary endpoint, an interval might accompany a risk difference, ratio or other prespecified contrast. The choice of contrast and interval method should reflect the trial design and analysis plan. No such estimate or interval is reported in the registry record. A calculation from summary statistics, if undertaken separately, would be an unadjusted recalculation and should not be confused with the sponsor's own analysis.

What does over-dispersion mean, and is it relevant?

Over-dispersion is a general statistical issue that arises when observed variability exceeds what a chosen model assumes. It is often relevant to count outcomes modeled as event rates, especially when observations vary more than a simple Poisson model allows. The primary endpoint is a count of participants with adverse events, not a reported recurrent-event rate. The registry record does not report a model for event counts or a recurrent-event analysis, so there is no basis for claiming that an over-dispersion adjustment was used or needed for the posted endpoint.

How should planning illustrations be read?

Sample-size illustrations are planning exercises, not observed results and not a measure of the study's achieved power. The stated assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. For time-to-event illustrations, the stated output is total events; for other outcomes, it is participants per arm for 80% power or another stated power level. These assumptions are not the trial's own design rationale. The registry record does not report the sample-size justification, and the primary safety outcome was not reduced to a single comparison for a planning calculation.

In general, power depends on the effect size, variability, design, analysis method and sample size. It cannot be inferred simply from whether a result is statistically significant, and a planning illustration does not establish the probability that the observed result is true. No observed-power claim is supported by the registry record. The listed enrollment of 25 should be interpreted as enrollment, not as proof that every planned cohort or treatment condition contributed data to the reported endpoint.

The registry record lists 55 outcome measures and 0 analyses. It identifies plasma concentration, AUC and Cmax outcomes for Part A as secondary outcomes. Their presence in the outcome list does not establish that results were reported or that all planned analyses were conducted. The PK result summaries, analysis methods and handling of missing PK measurements are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 55 outcome measures, including several pharmacokinetic outcomes and the primary safety endpoint. When a study evaluates multiple endpoints, doses, categories or time points, the chance of at least one apparently unusual result can increase if many formal tests are conducted. Statistical methods may address this through a prespecified hierarchy, adjustment procedure or a clearly descriptive interpretation. The registry record does not report a multiplicity strategy, a hierarchy among outcomes, or a formal hypothesis-testing plan. It also lists 0 analyses, so the registry entries do not identify a set of inferential tests for which an adjustment can be evaluated.

The primary endpoint includes more than a single comparison: adverse-event categories and multiple treatment groups are reported, with the placebo and 300 mg arms combined across Cohorts 1 and 2 under the stated similar dosing strategies. The registry record indicates that the outcome was not reduced to a single comparison. This supports reading the posted data descriptively rather than selecting one contrast after observing the counts.

Missing-data handling is not reported in the registry record. The record defines the Safety Population as randomized participants who received at least one dose, but does not describe how participants with incomplete follow-up, missing event information, withdrawal or incomplete treatment periods were handled. The at-risk counts are given for the listed groups; they should not be assumed to resolve all missingness questions.

The safety population definition differs from enrollment: enrollment was 25, while the endpoint reports treatment-specific counts for Part A, Cohorts 1 and 2. Given the crossover design, treatment-group counts are exposure-specific and should not be summed to estimate an overall participant count. The registry record does not provide a complete accounting of participants by cohort, treatment period and analysis population, nor does it report a separate per-protocol or pharmacokinetic population definition.

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

Serious adverse event counts are 0 in every Part A, Cohorts 1 and 2 treatment group with participants at risk: placebo, 30 mg, 60 mg, 120 mg, 300 mg, 600 mg and 800 mg. The listed groups also report 0 deaths. This means that no serious adverse events or deaths are recorded in those group summaries; it does not establish that the underlying risk is zero or that the same experience would occur in other populations or settings.

The registry's serious-event definition includes death, life-threatening events, inpatient hospitalization or its prolongation, persistent disability or incapacity, congenital anomaly or birth defect, and important medical events that may jeopardize a participant or require intervention to prevent a serious outcome. The non-serious event counts are reported separately and range across the listed Part A groups. An adverse event is temporally associated with study treatment under the registry definition, whether or not it is considered treatment-related. Thus, an event count is not by itself evidence that treatment caused the event.

Groups with 0 at-risk participants, including the listed Cohort 3 and Part B groups, contribute no observed safety information to these summaries. Dose level 7 was not conducted. The counts should be read as descriptive registry data, not as a definitive comparison of serious-event risk.

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

The registry record describes a first-in-human safety and pharmacokinetic study of GSK3186899 in healthy participants. Its primary safety outcome records participants with non-serious and serious adverse events in Part A, Cohorts 1 and 2, through Week 12. The posted counts show non-serious adverse events in each of the reported groups, while serious adverse events and deaths are recorded as 0 in those groups. This is the scope of the result: a descriptive account of the reported study groups and follow-up.

The counts do not establish causation. The adverse-event definition includes occurrences whether or not they were considered related to study treatment, and the registry record does not provide a formal causal attribution analysis in the registry record for this endpoint. Nor do the counts establish a comparative risk difference, ratio or dose-response relationship. No primary-outcome inferential analysis or confidence interval is reported, and the multi-group, crossover structure does not support treating the raw counts as a simple two-arm comparison.

The result also does not answer all of the trial's stated objectives. The registry lists single-dose plasma concentration, AUC and Cmax outcomes, and describes a food-effect component. It also describes planned repeat dosing in Part B. However, the PK summaries are not reported in the registry record details used for this interpretation, and the listed Part B groups have 0 participants at risk. The study is listed as terminated, but the reason for termination is not reported in the registry record.

Zero serious events in the observed group summaries should not be read as proof of safety in all circumstances. The study enrolled healthy participants and was a Phase 1 investigation; its results cannot establish safety or efficacy in people with Leishmaniasis or another patient population. The registry record does not report an efficacy endpoint or a clinical-benefit analysis. Its contribution is limited to the safety observations and study information recorded for the reported participants and treatment conditions.

13. Why This Trial Matters Statistically

This trial illustrates why clinical-trial results need to be interpreted in light of design, population and outcome definition. A first-in-human study is primarily concerned with initial safety, tolerability and pharmacokinetic characterization. The record's stated questions include single ascending doses, food effects and planned repeat doses, so the full research program extends beyond the primary adverse-event count.

The sequential crossover structure makes the treatment-group summaries different from results in a simple parallel-group trial. Participants in Part A could receive multiple regimens over separate periods, while Part B depended on review of Part A data. This affects how at-risk counts relate to enrollment and cautions against combining group counts or interpreting each group as a separate independent cohort. The registry's combined presentation of placebo and 300 mg data across Cohorts 1 and 2 also demonstrates how protocol-defined grouping can influence the form of safety summaries.

The record is statistically informative even though it does not supply an inferential treatment comparison. It identifies the analysis population definition, event categories, follow-up period and group-level counts. Those details allow readers to distinguish what was observed from what remains unanswered. The listed zero serious adverse events are a finding about the recorded observations, while the absence of confidence intervals, tests and PK summaries limits precision and broader interpretation.

Finally, the registry record shows the importance of separating a study's planned components from its reported data. Part B was conditional on Part A review, dose level 7 was not conducted, and the study status is terminated. These registry entries shape what can be learned from the posted summaries. They also show why enrollment alone cannot establish that every intended dose, cohort or outcome contributed to an analysis.

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 primary endpoint is reported for Part A, Cohorts 1 and 2, rather than for the entire set of study components. Cohort 3 and Part B treatment groups are listed with 0 participants at risk. This prevents the posted primary safety summaries from answering the food-effect safety question or providing an observed repeat-dose safety summary. Dose level 7 was not conducted because escalation stopped at dose level 6 (800 mg).

The crossover structure complicates simple comparisons across treatment groups. The same participant may contribute to more than one treatment condition, so group summaries should not be regarded as independent parallel-group samples or added to estimate an overall participant count. The record does not report a statistical method addressing period, sequence, within-participant correlation or carryover effects. It also does not give a detailed participant-flow account for each cohort and treatment period.

The listed outcome counts are descriptive. The registry record does not report a formal analysis for the primary safety endpoint, confidence intervals, p-values, a multiplicity plan, missing-data handling, sample-size justification or interim-analysis plan. Although sample-size planning assumptions are described, they are planning illustrations rather than the trial's own design justification or evidence of observed power.

The study is listed as terminated, but the reason is not reported in the registry record. The PK outcomes are listed, yet their result summaries are not reported in the registry record for this analysis. Enrollment was 25, but that total does not establish the number contributing to each analysis or treatment condition. Finally, the population consisted of healthy participants; the safety counts do not directly characterize outcomes in a patient population.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects — NCT03874234.
• Registry record last updated 2023-02-27; status last verified 2022-05.
• Results first posted 2023-02-27.
• 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.

18. Record Summary

NCT03874234 is a randomized, double-blind, placebo-controlled, Phase 1 first-in-human study of GSK3186899 in healthy participants. Its planned components included single ascending doses, a fed-versus-fasted comparison and repeat dosing. The study used a sequential crossover design and is listed as terminated. Enrollment was 25; the registry record gives a start date of 2019-04-30 and a primary completion date of 2019-10-17.

The primary outcome counted participants with non-serious and serious adverse events in Part A, Cohorts 1 and 2, through Week 12. The reported groups show non-serious events and 0 serious adverse events; each also records 0 deaths. Cohort 3 and Part B groups have 0 participants at risk in the listed summaries, and dose level 7 was not conducted. The registry lists pharmacokinetic outcomes but does not report their result summaries in the registry record for this interpretation. No inferential primary-outcome analysis, multiplicity plan or missing-data method is reported in the registry record.