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 Bioequivalence Study Between GSK3542503 Hydrochlorothiazide + Amiloride Hydrochloride 50 mg: 5 mg Tablets and Reference Product in Healthy Adult Participants Under Fasting Conditions (NCT03031496), a randomized phase 1 study. The primary outcome is Area Under the Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Hydrochlorothiazide and Amiloride Hydrochloride.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03031496 |
| Phase | Phase 1 |
| Condition | Hypertension |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 42 |
| Arms in the primary outcome | n/a |
| Lead sponsor | GlaxoSmithKline |
| Results posted | Yes |
2. Clinical Question
Population
Healthy adult participants enrolled in a phase I study. The registry record reports enrollment of 42. The primary pharmacokinetic population was defined as participants who completed the study and had primary pharmacokinetic parameters calculated for all treatment periods.
Intervention
A single oral dose of GSK3542503, a fixed-dose combination tablet containing hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg, administered under fasting conditions.
Comparator
A single oral dose of the reference product, Moduretic, containing hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg. Participants were assigned to one of two treatment sequences so that they received both products in separate periods.
Primary question
Whether the test and reference products have comparable exposure, assessed using the area under the plasma concentration-time curve from time zero to the last quantifiable concentration for hydrochlorothiazide and amiloride hydrochloride. The registry describes assessment using 90% confidence intervals for geometric mean ratios against a conventional bioequivalence range, but the estimates, intervals, range and conclusion are not reported in the registry record.
3. Trial Design
This was a phase I, randomized, open-label, single-dose, two-period crossover study. The registry record describes a balanced design with two treatment sequences: test product followed by reference, or reference followed by test. Each participant was intended to receive one dose of each product, in separate treatment periods. The registry lists enrollment of 42; its study summary describes the planned enrollment as approximately 42 participants at a single center.
Both products contained hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg. Treatment was administered orally after an overnight fast of at least 10 hours, with 240 mL of water. Food was not allowed for at least 4 hours after dosing, and water was restricted for the hour before and after administration. The treatment periods were separated by a washout period of at least 7 days and no more than 14 days. The study summary describes an expected participant duration of 5 to 7 weeks from screening to the last visit.
A crossover design compares treatments within participants rather than assigning each participant to only one product. In general, this can reduce the influence of stable differences between people on a treatment comparison. It also makes the treatment sequence, period and potential carryover relevant to interpretation. The registry describes an analysis of variance including sequence, subject within sequence, treatment and period as fixed effects. It does not report additional details about carryover assessment or the rationale for the design.
The study status is completed. The registry record gives a start date of 2017-03-17 and a primary completion date of 2017-04-10. It does not report the actual dates of individual participant visits or the timing of any analysis after data collection.
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 42 participants were enrolled and randomized to receive a single oral dose of study treatment in a cross-over manner.
Period 1
| Stage | Treatment A Followed by Treatment B | Treatment B Followed by Treatment A |
|---|---|---|
| STARTED | 21 | 21 |
| COMPLETED | 19 | 19 |
| NOT COMPLETED | 2 | 2 |
Reasons for not completing this period:
| Reason | Treatment A Followed by Treatment B | Treatment B Followed by Treatment A |
|---|---|---|
| Adverse Event | 2 | 0 |
| Withdrawal by Subject | 0 | 2 |
Period 2
| Stage | Treatment A Followed by Treatment B | Treatment B Followed by Treatment A |
|---|---|---|
| STARTED | 19 | 19 |
| COMPLETED | 19 | 19 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: PK Population comprised of All participants who completed the study and for whom primary PK parameters was calculated for all treatment periods.
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 | All Subjects |
|---|---|---|
| Participants analysed | 42 | |
| Age, Continuous | Years | 24.1 (SD 4.13) |
| Sex: Female, Male: Female | Participants | 14 |
| Sex: Female, Male: Male | Participants | 28 |
| Race/Ethnicity, Customized: Black or African American Heritage | Participants | 29 |
| Race/Ethnicity, Customized: White Heritage | Participants | 12 |
| Race/Ethnicity, Customized: Mixed Heritage | Participants | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Area Under the Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Hydrochlorothiazide and Amiloride Hydrochloride, measured over Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | Hour x nanograms/milliliter (h*ng/mL) |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, abbreviated AUC (0-t), for hydrochlorothiazide and amiloride hydrochloride. It is reported in hour x nanograms/milliliter (h*ng/mL). The endpoint summarizes drug concentration over time across the observed sampling interval; it is not a single concentration measurement. The registry specifies blood sampling from pre-dose through 48 hours after dosing, with multiple measurements on Day 1 and further measurements on Day 2 and Day 3.
For a bioequivalence assessment, exposure measures can be compared between the test and reference products. The registry states that the comparison used geometric mean ratios and their 90% confidence intervals, evaluated against a conventional bioequivalence range. A geometric mean is a measure suited to positive, often right-skewed pharmacokinetic data. The confidence interval describes uncertainty around the estimated ratio; whether it falls within the specified range is central to the stated assessment approach. The actual ratios, confidence intervals and range are not reported in the registry record, so the endpoint’s observed result and the bioequivalence conclusion cannot be described.
The registry also lists AUC from time zero to infinity, maximum concentration, time to maximum concentration, extrapolated AUC percentage and terminal half-life among secondary outcomes. These measures address other aspects of exposure and concentration-time behavior. Their results are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record provides the study design and the planned primary pharmacokinetic comparison, but it does not provide the estimates needed to interpret the observed endpoint. No geometric mean ratio, 90% confidence interval, endpoint summary by treatment, p-value or bioequivalence conclusion is reported in the registry record. The conventional bioequivalence range is also not stated. As a result, the record does not establish whether the test and reference products met the study’s stated bioequivalence assessment criterion.
This absence of results matters because a bioequivalence question is not answered merely by matching the listed ingredient strengths or by conducting a crossover study. The relevant evidence would include the treatment comparison and its uncertainty, interpreted using the prespecified or otherwise applicable acceptance range. Without the comparison estimate and interval, neither the direction nor the precision of the observed difference can be assessed from the registry record.
The design description does identify some features that shape interpretation. Participants received both treatments in randomized sequence, with a washout between treatment periods. In general, a crossover comparison uses within-participant information, while accounting for treatment period and sequence. The registry describes an analysis of variance with sequence, subject within sequence, treatment and period as fixed effects. It does not report the fitted model’s results or enough detail to evaluate whether its assumptions were examined.
The primary pharmacokinetic population was defined by study completion and availability of primary pharmacokinetic parameters for all treatment periods. The number included in that population and any exclusions are not reported in the registry record. The record therefore does not permit assessment of how the analysis population differed from the enrolled population or whether missing pharmacokinetic observations affected the comparison.
The listed safety counts describe adverse events by treatment period, not the primary pharmacokinetic endpoint. Serious adverse events were reported as zero in both treatment groups. Other adverse events were reported as 5 for Treatment A and 13 for Treatment B, with 40 participants at risk in each group. These figures should be read as registry-reported counts for the respective treatment groups; they do not supply the missing exposure estimates or resolve the bioequivalence question.
Overall, the available record supports a description of the planned comparison, design and selected safety counts. It does not support a quantitative conclusion about the primary pharmacokinetic result, the precision of that result or whether the stated bioequivalence criterion was satisfied. The endpoint results and the sponsor’s analysis are not reported in the registry record.
9. Statistical Methods Explained
The registry describes a pharmacokinetic comparison within a randomized, open-label crossover study. The central statistical idea is to compare exposure after the test product with exposure after the reference product, using measurements from participants who received both treatments. The following concepts explain the methods named in the record; they do not supply missing analysis details or results.
Why compare geometric means?
Pharmacokinetic measurements are positive quantities and can have a skewed distribution. A geometric mean summarizes multiplicative rather than additive variation. A ratio of geometric means expresses the test product’s exposure relative to the reference product’s exposure. A ratio near one would indicate similar estimated geometric means, but a point estimate alone would not describe uncertainty or determine whether the criterion was met. The actual geometric mean ratios are not reported in the registry record.
The record reports geometric coefficient of variation as the dispersion measure for the primary endpoint. In general, a coefficient of variation describes variability relative to the scale of a measurement. A geometric version is used with quantities analyzed on a multiplicative scale. The registry does not report the observed dispersion values, so variability in the study cannot be quantified from this record.
What does a confidence interval contribute?
A confidence interval gives a range of estimates compatible with the data and the method’s assumptions, and communicates the precision of an estimate. The registry says that bioequivalence was assessed using 90% confidence intervals for geometric mean ratios in relation to a conventional bioequivalence range. The actual intervals and the range are not reported in the registry record. Without both, it is not possible to determine whether the interval met the stated criterion. A confidence interval is not a guarantee that the true value lies within its limits, and it is not a substitute for reporting the estimate and analysis details.
What does the analysis of variance account for?
The stated analysis of variance included sequence, subject within sequence, treatment and period as fixed effects. In a crossover study, treatment identifies which product was administered, while period distinguishes the separate treatment occasions. Sequence represents the order in which treatments were received. Subject within sequence accounts for the fact that each participant belongs to a treatment-order group and contributes repeated treatment-period information. In general, modeling these features helps distinguish treatment-related variation from variation associated with order, period and participant.
The record does not report the model formula beyond its listed effects, the response transformation, estimation procedure, residual diagnostics, handling of influential observations, or any sensitivity analyses. It would be inappropriate to infer these details from the endpoint name or from common practice. The model’s numerical estimates and uncertainty are also absent.
Why is the crossover structure important?
In general, a crossover can control for stable between-participant differences because each participant receives both products. This advantage depends on usable measurements from both periods and on the design’s assumptions. A washout is intended to separate treatment periods, but the record’s washout duration alone does not establish whether carryover was absent. The registry does not report a carryover assessment, a period-specific result, or the number of participants with complete data for both periods.
Randomized treatment sequence helps avoid systematic assignment of one order over another. Open-label means masking was none, according to the registry record. For an objective concentration measurement, awareness of treatment does not by itself tell the reader whether measurement or analysis was biased; the record does not describe laboratory blinding or other safeguards. Those details are not reported in the registry record.
How should the planning illustrations be understood?
Planning illustrations are not observed study results. The registry’s stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect described as a fraction of the observed effect. The illustrations are based on the observed effect, not on the trial’s own design. They must not be read as observed power or as evidence that the trial was adequately powered for its primary bioequivalence objective. The illustration values themselves are not reported in the registry record.
In general, sample-size planning asks how many participants would be needed under specified assumptions to target a chosen precision or probability of detecting an effect. Such calculations depend on the assumed effect, variability, allocation and analysis. They do not show what the completed study found. The registry record does not report a design-stage sample-size justification or the assumptions used to choose enrollment of 42.
What cannot be inferred from the available analysis description?
The endpoint description identifies repeated blood sampling and the summary measure, but it does not provide the concentration data or treatment-level summaries. It also does not state the exact bioequivalence limits, any confidence-interval results, or the outcome of the analysis. The record lists 16 outcome measures and 6 analyses, but does not explain how multiplicity was handled across outcomes or analyses. It does not report a missing-data method, imputation procedure or sensitivity analysis.
Thus, the method description clarifies the intended comparison but is not enough to reconstruct the analysis or judge its result. General statistical principles can explain why geometric ratios, confidence intervals and crossover terms are relevant; they cannot fill in estimates, assumptions or decisions absent from the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 16 outcome measures and 6 analyses. It does not report whether the analyses were prespecified in a statistical analysis plan, which comparisons were confirmatory, or how multiplicity across endpoints or analyses was addressed. No adjustment method, hierarchy of outcomes, or distinction between confirmatory and exploratory analyses is reported in the registry record. Accordingly, the number of listed outcomes alone does not show how many formal statistical tests were performed or what error-control approach was used.
The primary pharmacokinetic population is described as participants who completed the study and had primary pharmacokinetic parameters calculated for all treatment periods. The record does not give the number in that population, the reasons for any exclusions, or the number with incomplete pharmacokinetic data. It does not report how missing samples or measurements were handled, whether any values were imputed, or whether sensitivity analyses examined the effect of missing data. Those details are not reported in the registry record.
The record describes one primary endpoint involving both hydrochlorothiazide and amiloride hydrochloride, and lists other pharmacokinetic, safety and laboratory outcomes. It does not clarify how the primary status was applied across the two substances or whether each had a separate decision criterion. The registry also states that the primary outcome has several categories or time points and was not reduced to one comparison. Therefore, a single numerical summary cannot be substituted for the analyses that are not reported.
For interpretation, missingness and multiplicity are distinct issues. Missing-data methods concern which observations contribute and how incomplete measurements are treated. Multiplicity concerns the interpretation of multiple outcomes or comparisons. Neither issue can be resolved from the endpoint list alone; the relevant plans and results are not reported in the registry record.
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 |
|---|---|---|---|
| Treatment A | 0 | 40 | 0.0% |
| Treatment B | 0 | 40 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Treatment A | 0 of 40 |
| Treatment B | 0 of 40 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Treatment A | 5 of 40 |
| Treatment B | 13 of 40 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Treatment A | Treatment B |
|---|---|---|---|
| Headache | Nervous system disorders | 3 of 40 | 3 of 40 |
| Dizziness | Nervous system disorders | 0 of 40 | 5 of 40 |
| Abdominal Pain | Gastrointestinal disorders | 0 of 40 | 2 of 40 |
| Ear Pain | Ear and labyrinth disorders | 0 of 40 | 1 of 40 |
| Diarrhoea | Gastrointestinal disorders | 0 of 40 | 1 of 40 |
| Crystal Urine | Investigations | 1 of 40 | 0 of 40 |
| Hyperkalaemia | Metabolism and nutrition disorders | 1 of 40 | 0 of 40 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 0 of 40 | 1 of 40 |
The registry reports serious adverse events for Treatment A and Treatment B separately. In each group, 40 participants were listed as at risk, and the serious adverse event count was 0. The registry also reports 0 deaths in each group. These are the posted serious-event figures and should be interpreted as counts within the treatment groups, not as a comparison of the primary pharmacokinetic endpoint.
For other adverse events, the reported counts were 5 for Treatment A and 13 for Treatment B, with 40 participants at risk in each group. Because this was a crossover study, the treatment groups refer to treatment periods and participants received both products according to sequence. The counts should not be interpreted as if the groups necessarily consisted of separate sets of people. The registry does not provide event-level details, timing, severity breakdowns for other events, or a statistical comparison of these counts.
A zero serious-event count in the registry does not establish that an event is impossible or that risk is absent. In general, safety counts are descriptive and depend on the population, observation period and event definitions used. The registry record does not report further detail about adverse-event ascertainment or follow-up beyond the listed treatment-period counts.
12. What the Result Does, and Does Not, Mean
This study was designed to compare pharmacokinetic exposure after a test fixed-dose combination tablet and a reference product in healthy adults under fasting conditions. Its primary endpoint was AUC (0-t) for hydrochlorothiazide and amiloride hydrochloride, and the stated bioequivalence approach used 90% confidence intervals for geometric mean ratios in relation to a conventional range. These details explain the question and the planned statistical framework.
They do not establish the outcome. The actual ratios, confidence intervals, endpoint summaries and bioequivalence conclusion are not reported in the registry record. The conventional range is also not reported. The record therefore cannot show whether the estimates were close, how precise they were, or whether the study met its stated assessment criterion. The study’s status as completed is not itself evidence of a particular result.
The registry describes a randomized crossover, with participants assigned to test-then-reference or reference-then-test sequences. In general, this design allows within-participant comparison and may reduce the effect of stable differences between participants. The record does not provide the complete analysis population or results needed to evaluate how the design performed in this study.
The listed safety counts show zero serious adverse events and zero deaths in each treatment group, alongside other adverse-event counts of 5 for Treatment A and 13 for Treatment B. These descriptive counts do not answer the primary exposure question and do not, on their own, establish comparative safety. The record does not report additional detail necessary for a fuller safety interpretation.
The study concerns pharmacokinetic measurements in healthy adults after single doses under fasting conditions. The registry does not report clinical outcome results, and the pharmacokinetic assessment described should not be treated as evidence of clinical benefit or harm. The appropriate conclusion from the record is limited: it documents a completed study and its intended analysis, while the primary result and its uncertainty are not reported in the registry record.
13. Why This Trial Matters Statistically
Bioequivalence studies rely on a clearly defined comparison and an uncertainty-based decision, not merely on whether two products contain the same stated ingredients and strengths. This record identifies the exposure measure, the two products, and the use of geometric mean ratios with 90% confidence intervals. Those are important components of a statistical question: what is being compared, on what scale, and how uncertainty is to inform interpretation.
The randomized crossover structure is also statistically relevant. Each participant was assigned to a treatment sequence and received both products in separate periods. In general, within-participant comparisons can reduce the influence of stable differences between people, while sequence and period terms address features of the treatment order. The registry describes these terms in its analysis of variance, making the intended framework clearer than a simple comparison of unrelated groups.
At the same time, this record illustrates why design descriptions and outcome evidence must be distinguished. The confidence intervals, geometric mean ratios, and conclusion are not reported in the registry record. Without them, readers cannot assess the magnitude or precision of the comparison or determine whether the stated criterion was met. A completed study and a specified model do not substitute for outcome reporting.
The safety entries also demonstrate the importance of reading denominators and design together. Participants received both treatments, so treatment-period counts are not necessarily counts from independent participant groups. The record reports serious events and other adverse events by treatment group, but does not provide a formal comparative analysis.
Statistically, the study matters as an example of how the target estimand, crossover design, exposure summary and confidence-interval criterion fit together. It also shows the limits of interpretation when the registry record contains methods and descriptive safety counts but not the primary estimates. Transparent reporting of results and analysis details is essential to evaluate both the statistical conclusion and its precision.
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 most important limitation for interpreting this specific record is that it does not report the primary endpoint estimates, geometric mean ratios, confidence intervals or bioequivalence conclusion. It also does not state the conventional bioequivalence range. Consequently, the central planned comparison cannot be evaluated from the registry record.
The record defines the pharmacokinetic population by completion and availability of primary parameters for all treatment periods, but does not report the number analyzed or the disposition of enrolled participants. The reasons for missing or unusable pharmacokinetic data, if any, are not reported in the registry record. This prevents assessment of how the analysis population relates to the enrollment of 42.
Although the registry gives the analysis-of-variance effects, it does not report the model’s detailed specification, response transformation, diagnostics, handling of unusual observations, or sensitivity analyses. It also does not report a carryover assessment. These are relevant details for judging how the crossover analysis was implemented, but they cannot be inferred from the design description.
The record lists multiple outcome measures and analyses without describing multiplicity handling or identifying the status of each analysis. It does not report a statistical analysis plan, missing-data strategy or outcome-level results for the secondary pharmacokinetic and laboratory measures. The safety data are limited to listed counts and do not include event-level descriptions or a comparative analysis.
Finally, the study involved healthy adults, single-dose administration, and fasting conditions. The registry record does not provide evidence about repeated dosing or clinical outcomes. These design features define the scope of the stated study question; no broader conclusion should be inferred from the record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Bioequivalence Study Between GSK3542503 Hydrochlorothiazide + Amiloride Hydrochloride 50 mg: 5 mg Tablets and Reference Product in Healthy Adult Participants Under Fasting Conditions — NCT03031496.
- Registry record last updated 2021-05-07; status last verified 2021-05.
- Results first posted 2018-08-31.
- 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
The registry describes a completed phase I, randomized, open-label, two-period crossover study of GSK3542503 versus Moduretic in healthy adult participants under fasting conditions. Both products contained hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg. Enrollment was 42, and each participant was intended to receive both treatments in one of two randomized sequences.
The primary endpoint was AUC (0-t) for hydrochlorothiazide and amiloride hydrochloride. The stated assessment used 90% confidence intervals for geometric mean ratios and an analysis of variance including sequence, subject within sequence, treatment and period. The primary endpoint estimates, confidence intervals and bioequivalence conclusion are not reported in the registry record.
The registry reports 0 serious adverse events and 0 deaths for each treatment group, with 40 at risk in each. Other adverse-event counts were 5 for Treatment A and 13 for Treatment B. The record does not report sufficient detail to interpret the missing primary results or make a broader clinical conclusion.