Relative Bioavailability Study of Marketed and Lower Dose Ambrisentan in Healthy Adult Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Relative Bioavailability Study of Marketed and Lower Dose Ambrisentan in Healthy Adult Participants (NCT04095286), a randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) After Administration of AMB Under Fasted Condition.

2. Clinical Question

The central question is how the measured peak plasma concentration for each study formulation compares with the reference tablet in this study population. The registry reports a ratio and a 90% confidence interval for each comparison. Those estimates describe the posted pharmacokinetic results and their statistical precision; they do not by themselves establish a clinical effect or settle whether a formulation meets a prespecified acceptance criterion. Such a criterion is not reported in the registry record.

3. Trial Design

This was a phase 1, randomized, open-label, single-center, three-period crossover study. The registry reports an enrollment of 29 and a completed status. The study began on 2019-09-30, and primary completion was recorded as 2019-12-17. The study summary says each participant’s total study duration was expected to be approximately 9 weeks.

In a crossover design, participants receive more than one treatment across different periods, rather than remaining in only one treatment group. Here, the registry lists sequences containing dispersed ambrisentan, an oral ambrisentan tablet, and reference ambrisentan. The arm descriptions include sequences with different treatment orders and refer to washout between periods, although several descriptions are truncated. The specific randomization procedure, sequence allocation counts, and washout duration are not reported in the registry record.

The study was open-label, meaning masking was not used. The registry identifies the sponsor as GlaxoSmithKline. Its summary describes a single-dose comparison intended to provide pharmacokinetic and safety information about a lower-dose formulation intended for pediatric use. Participants in this study were healthy adults, so the posted results describe observations in that population.

There is an internal detail to keep in view when reading the treatment descriptions. The intervention list calls the new formulation 1 mg, while the arm descriptions refer to single doses of 5 mg for the dispersed formulation and the oral tablet. The comparator is listed as reference 5 mg. The record does not explain the difference between the intervention label and the arm descriptions, so the dose wording should not be reconciled by assumption.

The registry lists 12 outcome measures and 6 analyses. The primary endpoint is a pharmacokinetic measure; safety outcomes include serious and non-serious adverse events and several laboratory, vital-sign, and ECG assessments. The registry record does not report the study’s sample-size justification or a fuller statistical analysis plan.

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 29 participants were enrolled at a single center in the United Kingdom.

Period 1 (4 Days) + Washout (7days)

Reasons for not completing this period:

Period 2 (4 Days) + Washout (7days)

Reasons for not completing this period:

Period 3 (4 Days) + Follow up (14 Days)

Analysis population for the primary outcome, as defined in the registry: PK Parameter Population. Only those participants with data available at the specified data points were analyzed.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) After Administration of AMB Under Fasted Condition, measured over Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose.

The primary endpoint is maximum observed plasma concentration, abbreviated Cmax. It represents the highest measured ambrisentan concentration in plasma among the scheduled post-dose observations. The registry lists blood sampling before dosing and at 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours after dosing. Concentration is reported in nanograms per milliliter.

General: Cmax is used in pharmacokinetic studies to describe the observed peak concentration after a dose. Comparing this measure across formulations can show whether the measured peak exposure differs in the study conditions. It is one part of a pharmacokinetic profile; by itself, it does not describe the full concentration-time pattern or establish a clinical benefit or harm.

The registry reports geometric means and geometric coefficients of variation for the treatment groups, alongside adjusted geometric mean ratios for the comparisons. Geometric summaries are commonly used for positive concentration measurements that may be skewed. A ratio expresses one treatment’s estimated geometric mean relative to another’s; a value of 1 would represent equal estimated geometric means. The registry does not report the adjustment model or a prespecified acceptance range for interpreting the ratios.

The primary analysis population is described as participants with pharmacokinetic parameter data, and only those with data available at the specified data points were analyzed. The number contributing to each arm-level summary is posted, but the record does not explain the reasons for missing measurements.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the geometric mean summarize?

The endpoint is a concentration measurement, and the registry summarizes it with a geometric mean. General: a geometric mean is calculated on a multiplicative scale and is often useful when positive measurements vary proportionally or are not symmetrically distributed on their original scale. It is different from an arithmetic mean, which averages the original measurements directly. The registry does not report the individual observations, so the posted arm summaries cannot be independently reconstructed from the information.

The geometric coefficient of variation describes variability on a relative scale. The posted values are 15.5 for the dispersed formulation, 19.2 for the oral tablet, and 29.3 for reference ambrisentan. These summaries characterize variation within each treatment’s observed data; they are not confidence intervals for the treatment comparisons. A group’s coefficient of variation should not be treated as a measure of the precision of its adjusted ratio.

How should a ratio be read?

The registry reports ratios of adjusted geometric means. The first comparison is dispersed formulation relative to reference, with an estimate of 1.03 and a 90% confidence interval of 0.96 to 1.11. The second is oral tablet relative to reference, with an estimate of 0.91 and a 90% confidence interval of 0.85 to 0.98. General: a ratio of 1 indicates equal values on the ratio scale; ratios above or below 1 indicate estimates above or below the comparator, respectively.

The word “adjusted” indicates that the posted estimate is not simply presented as a ratio of the raw arm-level summaries. The adjustment variables and statistical model are not reported in the registry record. It would therefore be inappropriate to infer which covariates or crossover terms were included, or to reproduce the sponsor’s estimate using only the arm-level geometric means.

What does a confidence interval communicate?

A confidence interval conveys uncertainty around an estimate. General: narrower intervals indicate greater statistical precision than wider intervals, considered on the same scale and under the same method. The 90% intervals show a range around each estimated ratio. They do not express the probability that a particular fixed value is true, and their interpretation relies on the analysis assumptions.

The first interval extends from 0.96 to 1.11 and includes 1. The second extends from 0.85 to 0.98 and lies below 1. These are statements about the reported interval limits, not a substitute for a decision rule. The registry does not report an equivalence or acceptance margin. Without such a margin, the intervals cannot be used to declare that a treatment comparison meets a prespecified equivalence standard.

Why is the crossover structure relevant?

General: in a crossover study, treatment comparisons can use measurements from the same participants under different treatment conditions. This may reduce variability attributable to stable differences between participants. At the same time, period, sequence, and carryover considerations can matter. The registry describes randomized sequences and washout periods, but the washout duration and the analysis methods for these design features are not reported in the registry record. No particular model or assumption should be attributed to the study based on the design description alone.

The posted group counts for the primary endpoint are 27 for dispersed formulation, 25 for oral tablet, and 26 for reference. Because participants could contribute data under more than one treatment, these counts should not be added as if they necessarily represented separate groups of people. The record does not report the number of participants with complete data across all periods or explain why the endpoint counts vary.

What can be learned from the planning illustrations?

The sample-size section contains planning illustrations based on an observed effect, under stated assumptions about significance level, allocation, and a normal approximation. General: such illustrations address how many participants per arm might be planned for a future comparison under those assumptions. They are not the number enrolled or analyzed in this study, and they are not observed power. The registry does not report the trial’s own sample-size justification, so the illustrations should not be read as evidence about the original design decision.

The record categorizes the outcome as not reduced to one comparison and notes that values are missing or not estimable for a two-arm comparison. Accordingly, there is no basis for presenting a single recalculated two-arm result. The posted adjusted ratios and confidence intervals are the available comparison results. The statistical method used to obtain them is not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry posts the sponsor’s analyses as ratios of adjusted geometric means, with 90% confidence intervals. For dispersed ambrisentan versus reference, the ratio is 1.03 (0.96 to 1.11); for the oral tablet versus reference, it is 0.91 (0.85 to 0.98). These are the results to use when describing the study’s reported comparisons.

The record does not provide a separate recalculated estimate for these comparisons. It also categorizes the outcome as not reduced to one comparison and notes that values are missing or not estimable for a two-arm comparison. The arm-level geometric means are descriptive summaries and cannot reproduce an adjusted crossover estimate without the analysis model and participant-level data.

No discrepancy is flagged in the record. The method used for the sponsor’s adjustment, the model terms, and any prespecified decision limits are not reported in the registry record. The posted analysis therefore supports a careful account of the reported ratios and their intervals, but not an independent reconstruction or a conclusion about whether a formal criterion was satisfied.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and 6 analyses. The primary endpoint is Cmax; secondary outcomes include serious and non-serious adverse events, vital signs, ECG findings, hematology, clinical chemistry, and urinalysis assessments. When a study examines multiple outcomes or comparisons, general statistical practice recognizes that the chance of at least one apparently unusual result can depend on how many tests are considered and how they are handled.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or a statistical plan explaining how the primary and secondary analyses were prioritized. It also does not report whether interim analyses were planned or performed. No assumption about such procedures should be made from the number of posted outcomes alone.

The primary pharmacokinetic population is described as participants with parameter data, with only those having data at specified points analyzed. The arm counts are 27, 25, and 26. The record does not explain the difference in counts, provide a flow of missing observations, or describe imputation or other missing-data methods. It is therefore not possible to assess from the posted record whether missing data could have affected the estimates.

The reported ratios are adjusted, but the adjustment model and analysis population details beyond the brief population description are not reported in the registry record. The record also does not state the number of participants with complete measurements across all periods. These omissions limit independent evaluation of the statistical analysis, especially for a crossover design where observations across treatment periods are related.

The registry provides no prespecified acceptance margin for interpreting the ratio intervals. Consequently, the reader can describe the estimates and their precision but cannot infer a formal equivalence decision or the criteria used by the sponsor. The posted analyses should be understood in that context rather than as a complete account of the study’s statistical plan.

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 2% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event summary reports zero serious adverse events in each treatment group: 0 among 27 participants for ambrisentan dispersed in water, 0 among 25 for the oral tablet, and 0 among 26 for reference ambrisentan. It reports zero deaths in each group. The numbers at risk are the participants represented in the respective summaries.

For other adverse events, the summary reports 5 participants among 27 for the dispersed formulation, 7 among 25 for the oral tablet, and 5 among 26 for reference ambrisentan. These are participant counts, not necessarily counts of individual event episodes. The registry lists a secondary outcome covering non-serious adverse events at least 2%, but the adverse-event summary does not provide event terms; the top serious terms list is empty.

General: a count of zero observed serious events means none were recorded in these posted group summaries; it does not establish that an event cannot occur. These figures describe safety observations in this study and should not be treated as a comparative safety conclusion. The registry does not provide detailed event narratives or a fuller account of how adverse events were collected and coded.

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

The results describe pharmacokinetic measurements after single-dose administration in healthy adult participants. The primary endpoint was maximum observed plasma concentration, and the registry reports adjusted geometric mean ratios for two comparisons with reference ambrisentan. The dispersed formulation estimate was 1.03, with a 90% confidence interval from 0.96 to 1.11. The oral tablet estimate was 0.91, with a 90% confidence interval from 0.85 to 0.98.

These estimates do not establish that one formulation is clinically better or worse, nor do they answer a question about treatment outcomes in people with pulmonary hypertension. The study summary describes healthy adults and a pharmacokinetic and safety objective. It says the lower-dose formulation is intended for pediatric use, but this study did not enroll children according to the posted description. The findings therefore should not be represented as direct observations in pediatric participants.

The interval estimates also do not, by themselves, establish equivalence. A formal interpretation would require a prespecified margin and appropriate analysis details, which are not reported in the registry record. Likewise, the posted Cmax summaries do not describe every pharmacokinetic feature or establish a clinical consequence.

The intervention description contains a dose-label inconsistency: the intervention list identifies the new formulation as 1 mg, while arm descriptions refer to 5 mg doses for the dispersed formulation and oral tablet. The record does not resolve that inconsistency. It is important to preserve that uncertainty rather than infer which dose wording should govern interpretation.

In short, the registry presents quantitative relative Cmax estimates, their confidence intervals, and limited safety counts. Those observations can be described as results of this study, but conclusions beyond the population, endpoint, and methods actually reported would require information not available in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why pharmacokinetic results need to be read on the scale and in the design in which they were reported. The primary summaries are geometric, and the treatment comparisons are ratios of adjusted geometric means. Reading the ratios alongside their confidence intervals gives more information than relying only on the arm-level means or on a single point estimate.

The crossover structure is also statistically important. Participants received treatments across multiple periods, so the data are not simply independent parallel groups. General: crossover designs can make within-participant comparisons useful, but analysis details matter, including how period and sequence are handled. Those details are not reported in the registry record, which limits independent assessment of the posted estimates.

The record also demonstrates the distinction between an observed study result and planning calculations. The sample-size section presents planning illustrations based on an observed effect; such illustrations are not observed power and do not replace the trial’s own design rationale. The original sample-size justification is not reported in the registry record.

Finally, a numerical ratio close to 1 is not a complete statistical conclusion. The confidence interval, prespecified comparison criterion, analysis population, and model all matter. Here the intervals are reported, but the acceptance margin and detailed model are not. Reporting those elements clearly is essential for readers to distinguish a descriptive pharmacokinetic comparison from a formal decision about equivalence or clinical relevance.

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.

Several trial-specific limitations affect interpretation of the registry results. First, the intervention list and arm descriptions do not use consistent dose wording: the new formulation is labeled 1 mg in the intervention list, while the sequence descriptions refer to 5 mg doses. The registry record does not explain this difference, so the intended dose comparison cannot be clarified from the posted descriptions alone.

Second, the report gives adjusted geometric mean ratios but does not identify the statistical model, adjustment variables, or treatment of period and sequence effects. These omissions make it difficult to independently assess the crossover analysis or reproduce its estimates from the arm-level summaries.

Third, the endpoint counts differ across treatment summaries, and the record does not explain missing measurements or report the number of participants with complete data across all periods. The analysis population is described only as participants with pharmacokinetic data available at the specified points. The impact of missing data cannot be evaluated from the posted information.

The registry does not report an acceptance margin, detailed sample-size justification, multiplicity procedure, interim analysis plan, or full statistical analysis plan. It also does not provide detailed adverse-event terms in the summary. These missing details constrain formal interpretation and independent evaluation; they do not change the reported estimates, but they limit what can responsibly be concluded from them.

Finally, the study involved healthy adults and a single-dose pharmacokinetic comparison. Its registry results should not be generalized to clinical outcomes or to pediatric participants based on the record alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Relative Bioavailability Study of Marketed and Lower Dose Ambrisentan in Healthy Adult Participants — NCT04095286.
• Registry record last updated 2020-08-06; status last verified 2020-07.
• Results first posted 2020-08-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT04095286 is a completed phase 1, randomized, open-label, single-center, three-period crossover study of ambrisentan formulations in healthy adults. Enrollment was 29. The study began on 2019-09-30 and primary completion was recorded as 2019-12-17.

The primary endpoint was maximum observed plasma concentration under fasted conditions. The registry reports adjusted geometric mean ratios versus reference ambrisentan for the dispersed formulation and oral tablet, each with a 90% confidence interval. The primary analysis counts were 27, 25, and 26 across the three treatment summaries. Safety summaries report no serious adverse events or deaths, alongside other adverse-event participant counts.

The record does not report a detailed statistical analysis plan, acceptance margin, or sample-size justification. Its intervention label and arm descriptions also differ in dose wording. These gaps should be kept in view when interpreting the posted results.