Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects (NCT02742766), a randomized phase 1 study. The primary outcome is Part 1: Number of Participants With Abnormal Findings in Physical Examinations.

2. Clinical Question

This question fits the study’s phase I focus on the safety and tolerability of GSK3008356. The registry describes single-dose and repeated-dose evaluation in healthy subjects and repeated-dose evaluation in obese subjects; the primary outcome is limited to Part 1. The registry record does not report a hypothesis or a prespecified statistical comparison for this endpoint. The counts can therefore describe the recorded findings by cohort, but they do not by themselves establish whether the frequency of abnormal findings differed between treatment and placebo.

3. Trial Design

The registry record describes NCT02742766 as a completed phase I, randomized, placebo-controlled, double-blind (sponsor unblind), parallel study. The sponsor was GlaxoSmithKline. Enrollment was 104. The study start date was 2016-03-14, and primary completion was 2017-06-16. The condition is listed as Healthy Volunteers.

The study had three parts. Part 1 was a single- and multiple-dose, dose-rising study in healthy subjects, with sequential cohorts and matching placebo. The listed Part 1 dose groups cover a range of schedules, including single doses, twice-daily schedules, and repeated hourly doses. The primary physical-examination outcome is reported only for Part 1, up to Day 8. Part 2 was a 14-day repeat-dose, dose-rising study in healthy subjects. The registry summary says its cohorts used morning or evening dosing schedules. Part 3 was a 28-day repeat-dose study in obese subjects, with three parallel cohorts.

The study summary says data from prior dose cohorts would be available before escalation decisions in Parts 1 and 2, and before the Part 3 parallel cohorts began. It also describes a dose-escalation meeting to review data and document whether to proceed or make alterations if indicated. The registry record does not report the meeting’s decisions or detailed procedures for making them.

Part 1 and the broader trial should not be conflated. Although the record describes all three parts and the overall enrollment, the primary endpoint results presented for interpretation are Part 1 results. Part 2 and Part 3 safety groups appear in the adverse-event record, but they do not contribute to the Part 1 physical-examination outcome. The exact allocation within each part and the number assigned to each treatment schedule are not stated as a complete allocation scheme 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: This study was planned to be conducted in 3 parts: Part 1 (single-day dosing) and Part 2 (repeat dose) dose-rising study in healthy participants and Part 3 (repeat dose) in obese participants. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Only the first 6 of 19 groups are shown.

Part 1 (Up to 8 Days)

Part 2 (Up to 22 Days)

Reasons for not completing this period:

Part 3 (Up to 36 Days)

Analysis population for the primary outcome, as defined in the registry: Safety Population comprised of all participants who received at least one dose of study medication.

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: Part 1, Cohort 9 was cancelled per emerging data that lowered the future no observed adverse event level (NOAEL) and made the dose level and strategy irrelevant. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2.

Only the first 6 of 20 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Number of Participants With Abnormal Findings in Physical Examinations, measured over Up to Day 8.

The primary endpoint counts participants with abnormal findings on physical examinations in Part 1, with assessment up to Day 8. The registry defines the safety population as participants who received at least one dose of study medication. A complete physical examination covered cardiovascular, respiratory, gastrointestinal, dermatologic, and neurological systems, as well as height and weight. Height was measured and recorded only at screening. A brief examination covered skin, lungs, the cardiovascular system, and the abdomen, including liver and spleen. Weight was recorded with the brief examination but was not part of that examination.

Physical examinations are used in safety monitoring to identify findings that may warrant clinical review during a study. A participant count makes the outcome readable as a simple tally within each cohort. It does not indicate the type, seriousness, duration, or clinical importance of any abnormal finding, and it does not show whether a finding was new or present before treatment unless those details are reported separately. Those details are not reported for this primary endpoint in the registry record.

The measure is therefore descriptive at the level available in the posted results. It is not a continuous measure of change in physical status, nor does the count itself estimate a causal effect of GSK3008356. Interpretation depends on the cohort context, the examination procedures, and the completeness of outcome recording. The registry record presents a Part 1 count endpoint and does not report an inferential analysis for it.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a binary participant-level event summarized as a count in each Part 1 cohort. A participant either contributed to the count of abnormal physical-examination findings or did not, according to the recorded endpoint classification. The record reports the group size and event count for each listed cohort, rather than an estimate that combines cohorts or adjusts for differences among them.

What does a count show?

A count gives the number of participants meeting the endpoint definition. It is easy to interpret as a tally, but it does not account for differences in group size by itself. Comparisons based on counts alone can be misleading when the groups differ in size. A rate or proportion can make group sizes more comparable, but no such value should be inferred from the posted counts. The results remain the reported counts and group sizes.

General statistical principle: a binary outcome can be analyzed using methods that compare event probabilities, such as a difference in proportions or a model for binary data. Those methods require a defined comparison and assumptions about the data and analysis. The registry record does not report such a model or a formal primary comparison for this endpoint. A result for several dose cohorts should not be transformed into a single treatment-versus-placebo estimate unless the analysis plan specifies how that pooling is justified.

Why does uncertainty matter?

An observed count is one realization from the participants enrolled in a study. A confidence interval is a way of expressing the statistical uncertainty around an estimated quantity, such as an event probability or a treatment contrast. It gives readers a range of values compatible with the data and the method used, rather than suggesting that the observed result is exact. General statistical principle: intervals tend to be less precise when the data contain little information, including when groups are small or events are uncommon. The registry record does not report confidence intervals for the physical-examination counts.

A p-value, when used in a prespecified analysis, describes how compatible the data are with a specified null model under its assumptions. It is not a measure of clinical importance and does not give the probability that a treatment works. No p-value is reported for this primary endpoint, and the record lists no analyses. Accordingly, there is no posted significance test to interpret.

How should the cohort structure be handled?

Part 1 uses multiple dose cohorts and schedules, while the study as a whole also includes Parts 2 and 3. These groups have different roles and participant contexts. Part 1 was dose-rising in healthy subjects; Part 2 involved 14 daily repeat doses in healthy subjects; and Part 3 involved 28 daily repeat doses in obese subjects. A direct combination of their results would require a clear scientific rationale and a prespecified analysis. The registry record does not report such a combined primary analysis. The physical-examination endpoint under discussion is explicitly a Part 1 outcome.

The registry also describes review of earlier cohort data before escalation decisions. That description is relevant to the study conduct, but the statistical details of any review, including formal decision rules or interim analysis methods, are not reported in the registry record. It would be inappropriate to infer those procedures from the general description of dose escalation.

What do the planning illustrations represent?

Any sample-size figures based on the observed effect are planning illustrations, not observed power. The stated assumptions describe a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such calculations explore how a future design might perform under specified assumptions. They do not change the interpretation of the current observed counts, and they are not the trial’s own design justification. The sample-size justification is not reported in the registry record.

General statistical principle: post hoc planning based on an observed effect can be unstable because that estimate may be imprecise, especially when the outcome is uncommon and groups are small. Planning should account for the intended endpoint, target effect, analysis method, allocation, and expected missingness. The registry record does not provide those elements as a complete sample-size rationale for this endpoint.

Finally, the primary outcome is tied to the safety population, defined as participants who received at least one dose. This population definition is not necessarily interchangeable with an intention-to-treat population. The record does not describe an alternative analysis population, an imputation procedure, or rules for handling incomplete physical examinations. Those omissions limit assessment of how fully the observed counts represent all randomized participants.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Part 1- Placebo", "Part 1-Cohort A1: GSK3008356 5 mg", "Part 1-Cohort A2: GSK3008356 10 mg", "Part 1-Cohort A3: GSK3008356 30 mg", "Part 1-Cohort A4: GSK3008356 75 mg", "Part 1-Cohort A5: GSK3008356 200 mg")
n      <- c(20, 6, 6, 6, 6, 6)
events <- c(2, 1, 0, 1, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Part 1- Placebo  20  2  10.0  1.2  31.7  2.8  30.1  3.0  30.4
ARM  Part 1-Cohort A1: GSK3008356 5 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part 1-Cohort A2: GSK3008356 10 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part 1-Cohort A3: GSK3008356 30 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part 1-Cohort A4: GSK3008356 75 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part 1-Cohort A5: GSK3008356 200 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 46 outcome measures and 28 posted secondary outcomes, spanning physical examination, safety, pharmacokinetics, and pharmacodynamics. When many outcomes or dose-cohort comparisons are examined, the chance of at least one apparently unusual result can increase. General statistical principle: multiplicity procedures or a prespecified hierarchy can help control how findings are interpreted across multiple tests. The registry record does not report a multiplicity adjustment, a testing hierarchy, or a detailed statistical analysis plan for the primary physical-examination endpoint.

The record lists no analyses for the posted results. It therefore does not provide a reported hypothesis test or an explanation of how multiple comparisons were handled. The descriptive counts can be stated as recorded, but they should not be treated as a set of confirmatory findings or ranked by apparent differences across dose cohorts.

The registry defines the safety population as participants who received at least one dose of study medication. It does not explain how missing physical-examination assessments were handled, whether any observations were imputed, or how participants without an evaluable examination were classified. Missing-data procedures and the number of missing endpoint observations are not reported in the registry record. This prevents a full assessment of whether the cohort counts reflect complete observation of the safety population.

The registry’s enrollment figure does not establish the analysis population for this specific endpoint. Part 1, Part 2, and Part 3 have different participants and outcome roles, and the primary result is restricted to Part 1. The record does not describe how randomization, dose cohort membership, or any exclusions were handled in an inferential analysis of the primary outcome.

12. 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 serious adverse-event record lists 0 serious adverse events in the placebo and active Part 1 groups with participants at risk, and 0 deaths in those groups. It also lists 0 serious adverse events in the Part 2 groups with participants at risk. No serious adverse-event terms are listed. The Part 3 groups have 0 participants at risk in the posted safety record, so their zero serious-event counts cannot be read as evidence that no serious events occurred among participants who received treatment.

The adverse-event record separately reports other, non-serious adverse events. Those are not the primary physical-examination outcome, and their counts should not be substituted for it. A participant may have an adverse event without meeting the physical-examination endpoint, and the registry record does not provide a link between these outcome categories.

These safety figures are descriptive. A zero count in the posted record means no event was recorded in that listed group for the category shown; it does not establish that the underlying risk is absent. The record does not provide confidence intervals or comparative analyses for serious adverse events. It also does not provide detailed information about event duration, attribution, or clinical course. Consequently, the serious-event data should be interpreted within the groups and follow-up recorded, without extending the conclusion to unrepresented participants or beyond the study observation.

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

The primary result means that the registry records a small number of abnormal physical-examination findings in some Part 1 cohorts and no such findings in others. The placebo group had 2 recorded participants with abnormal findings. Among active dose groups with reported participants, the result ranged from 0 to 1 in the listed cohorts. The 200 mg evening-dose cohort has no evaluable group size or outcome value in the posted primary result. These statements describe the recorded endpoint; they do not establish why a finding occurred.

The result does not show that GSK3008356 caused or prevented an abnormal physical-examination finding. There is no reported effect estimate, uncertainty interval, p-value, or adjusted analysis for this endpoint. The number of participants with findings alone does not describe their nature, severity, or relationship to study medication. Nor does it establish a dose-response pattern across groups with different dosing schedules.

The result also does not summarize all safety outcomes. The study included separate safety monitoring and pharmacokinetic and pharmacodynamic objectives, and the registry lists many outcome measures. A physical-examination count cannot substitute for adverse-event detail, laboratory findings, or other clinical assessments. The separate serious adverse-event record has its own scope and should be read independently.

The study’s phase I context matters. The stated objectives focus on characterizing safety, tolerability, and preliminary PK and PD across healthy and obese subjects. The primary endpoint is from Part 1 and has a timeframe up to Day 8. It cannot answer questions about longer-term outcomes or about Part 3 participants with obesity. Findings from this endpoint should not be generalized beyond the population, schedules, and observation described in the registry.

In short, the posted result is a descriptive account of Part 1 physical-examination findings. It is not evidence of a clinical benefit, a definitive safety conclusion, or a comparative estimate of treatment effect.

14. Why This Trial Matters Statistically

This trial illustrates an important distinction in early-phase research: a study may collect many kinds of data while its registry-listed primary endpoint remains a straightforward descriptive count. The main statistical task is to keep the interpretation aligned with the outcome actually reported. A tally of participants with abnormal physical-examination findings is not equivalent to a causal comparison or a complete safety profile.

The dose-cohort structure also matters. Part 1 includes several schedules, while later parts differ in duration and population. Treating all groups as interchangeable would obscure the study design and could produce an inappropriate summary. Reading each cohort in context helps prevent a count from being mistaken for a common effect across different doses and schedules.

The record also demonstrates why uncertainty and analysis details matter even for simple outcomes. A count can be easy to understand, but small group sizes and uncommon events leave limited information for comparisons. Confidence intervals, an analysis plan, and explicit missing-data methods would help readers assess precision and the way observations were handled. Those statistical details are not reported for this endpoint in the registry record.

Finally, the registry describes dose-escalation review and multiple outcome domains. That context indicates that safety and preliminary PK and PD were central to the study, but it does not reveal the specific decision rules or how the many outcomes were prioritized analytically. Clear reporting of these decisions is important for distinguishing exploratory observations from confirmatory claims. The available physical-examination result supports careful description, not stronger inference.

15. 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 limited to Part 1 and to physical-examination findings up to Day 8. It does not represent the 14-day repeat-dose study in healthy subjects or the 28-day repeat-dose study in obese subjects. Conclusions about the primary endpoint therefore cannot be extended to those parts or populations.

The outcome is reported as counts by cohort. The registry does not provide a definition of what qualified as an abnormal finding beyond the examination descriptions, nor does it describe the individual findings, their severity, their timing, or whether they were considered related to study medication. It also does not report a treatment-effect estimate, confidence interval, p-value, or adjusted comparison for this endpoint.

The reported cohort sizes are limited, and one listed cohort has a group size of 0 with no primary outcome value. The registry does not explain this cohort’s status in the primary results. Missing physical-examination data, exclusions, and imputation procedures are not reported in the registry record, making it difficult to assess completeness of outcome capture.

The registry lists many outcomes but does not report the statistical analysis plan or how multiplicity was addressed. It also does not provide the sample-size justification for this endpoint. The broad study description mentions review before dose escalation, but formal interim-analysis methods and decision rules are not reported in the registry record. These limitations make the available endpoint most suitable for descriptive interpretation and constrain comparisons across dose groups.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects — NCT02742766.
• Registry record last updated 2019-07-24; status last verified 2019-07.
• Results first posted 2019-01-15.
• 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.

19. Record Summary

NCT02742766 is a completed phase I randomized, placebo-controlled, double-blind (sponsor unblind), parallel study sponsored by GlaxoSmithKline. The registry reports enrollment of 104, a start date of 2016-03-14, and primary completion on 2017-06-16. The study had three parts involving single or repeated doses of GSK3008356 and matching placebo in healthy and obese subjects.

The primary outcome described in the posted results is the number of Part 1 participants with abnormal physical-examination findings up to Day 8. The registry defines the safety population as participants who received at least one dose. Cohort counts are descriptive; the record does not report an inferential comparison for this endpoint. Statistical analysis details, missing-data procedures, and the sample-size justification are not reported in the registry record.