Relative Bioavailability Study Between Two Formulations Containing Ambroxol Hydrochloride: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Relative Bioavailability Study Between Two Formulations Containing Ambroxol Hydrochloride (NCT02572609), a registered phase 1 study. The primary outcome is Cmax.

2. Clinical Question

3. Trial Design

This was a phase 1 study with a crossover model, completed after starting in 2011-11 and reaching primary completion in 2011-12. It was sponsored by Boehringer Ingelheim. The masking designation is none. The study population is described as healthy, and the intended comparison was between ambroxol hydrochloride soft pastilles and Mucosolvan® adult syrup.

In general, a crossover study exposes participants to more than one treatment in different periods, allowing comparisons that can account for differences between participants. The registry’s crossover designation does not, by itself, establish the treatment sequence, period structure, washout interval, or how period and sequence effects were handled. Those details are not reported in the registry record.

The allocation field is not stated, and the registry’s description cautions that this is not a randomized comparison and that the arms are not a like-for-like control comparison. Accordingly, the crossover label should not be taken as evidence that treatment order was randomized or that all design features needed for an unbiased comparison are documented.

The pharmacokinetic set included 36 subjects with one evaluable value for each formulation for the primary pharmacokinetic endpoints, Cmax and AUC0-t, and without important protocol violations relevant to their statistical evaluation. This is an analysis-population description, not a report of the number initially enrolled. Enrollment, exclusions, treatment sequence, and the number completing each stage are not reported in the registry record.

The record names two drug interventions but does not describe administration details in the arm descriptions. Dose, timing of administration, food conditions, and other conduct details are not reported in the registry record. The study’s stated purpose was relative bioavailability; the record does not give a numerical result establishing the direction or size of a formulation difference.

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: The crossover design 2x2 was used in the study. This is a conventional nonreplicated design with two formulations, two periods, two sequences (RT and TR) where each individual is randomly allocated in one of these sequences.

Period 1: Treatment Period 1 + Washout

Period 2: Treatment Period 2

Analysis population for the primary outcome, as defined in the registry: The pharmacokinetic set (PK Set): 36 subjects provided 1 evaluable value of reference product and 1 evaluable value of test product for the primary PK endpoints (Cmax and AUC0-t) without important protocol violations with respect to the statistical evaluation of PK endpoints.

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: Treated set (TS): 36 subjects took 1 dose of reference product and 1 dose of test product.

6. Primary Endpoint

The registry lists the primary outcome as Cmax, measured over 0:00h (hours), 0:15h, 0:30h, 0:45h, 1:00h, 1:15h, 1:30h, 1:45h, 2:00h, 2:20h, 2:40, 3:00, 3:30h, 4:00h, 5:00h, 6:00h, 8:00h, 12:00h, 16:00h, 24:00h, 36:00h and 48:00h.

Cmax is the maximum plasma concentration achieved after administration. It is a pharmacokinetic measure of the highest observed concentration over the specified sampling period. The registry lists Cmax in ng/mL and describes it using a geometric mean with geometric coefficient of variation as the dispersion measure.

For this study, the listed timeframe includes scheduled sampling from 0:00h through 48:00h, with multiple intermediate times. That schedule indicates when concentration measurements were planned or taken for the endpoint; it does not itself provide any concentration values. No Cmax values, comparison estimate, or uncertainty interval are reported in the registry record.

In general, Cmax is used in bioavailability comparisons because it characterizes peak systemic exposure. It is distinct from a measure of exposure accumulated across time, such as AUC. The registry’s pharmacokinetic-set description names both Cmax and AUC0-t as primary pharmacokinetic endpoints, while the listed primary outcome is Cmax. Numerical results for AUC0-t are not reported in the registry record.

Geometric summaries are commonly used for pharmacokinetic measures that are analyzed on a multiplicative scale. The geometric coefficient of variation describes relative variability rather than variability in the original units. These summary conventions do not reveal whether the formulations differed: that requires reported estimates and their uncertainty, which are absent from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies Cmax as the primary outcome and describes it as the maximum plasma concentration achieved. It specifies a geometric mean and geometric coefficient of variation. However, it does not report the numerical values or the statistical test used for the comparison.

What does a geometric summary mean?

General: A geometric mean is suited to measurements treated on a multiplicative scale. It can be understood as a central summary after working with logarithms and then returning to the original scale. A geometric coefficient of variation describes relative spread, rather than spread in the original measurement units. For pharmacokinetic outcomes, these summaries can be useful when values vary proportionally. Their use does not, by itself, establish that a particular analysis was appropriate or that a formulation comparison met any criterion.

The registry lists concentration in ng/mL and describes measurements at scheduled times from 0:00h to 48:00h. It does not report the observed concentrations, how Cmax was derived from those measurements, or whether any sampling values were missing. A scheduled sampling framework is not a substitute for the outcome results.

How should the crossover model be understood?

General: A crossover design can compare treatments within the same participants, which may reduce the influence of stable differences between people. Interpretation also depends on treatment order, period effects, possible carryover, and the analysis used. The registry identifies a crossover model but does not report the sequence, period structure, washout, or statistical handling of these considerations. Allocation is not stated, and the record cautions that the comparison is not randomized and the arms are not a like-for-like control comparison. No specific crossover analysis should therefore be inferred.

What can be said about statistical uncertainty?

General: A confidence interval communicates uncertainty around an estimated effect; a narrower interval indicates greater precision under the model and assumptions used. A p-value addresses compatibility of data with a specified null hypothesis under a particular analysis. Neither quantity explains the clinical or pharmacokinetic importance of an effect on its own. The registry record does not report a confidence interval, p-value, or numerical treatment effect for Cmax.

The geometric coefficient of variation is a variability summary, not a confidence interval for the difference between formulations. It cannot be used alone to determine whether the formulations differ or how precisely a contrast was estimated. The absence of reported estimates means that neither precision nor statistical significance can be evaluated from the registry record.

How should planning illustrations be interpreted?

The stated planning illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes the effect to detect as a stated fraction of the observed effect. These are planning assumptions for an illustration based on the observed effect, not a report of the trial’s original design or a statement of observed power. The trial’s own sample-size justification is not reported in the registry record.

General: Sample-size planning asks how many participants would be needed under specified assumptions to detect an effect with a chosen operating characteristic. Such an illustration depends on the assumed effect size, variability, allocation, and analysis. It does not show that the completed study had a particular probability of success, and it cannot replace the observed estimate and its uncertainty. The registry record does not provide numerical pharmacokinetic outcomes from which to assess the observed effect directly.

The record also mentions AUC0-t in defining the pharmacokinetic set, but does not give an outcome estimate or a method for its analysis. The exact statistical model, covariates, treatment of period or sequence, missing-data approach, and any prespecified decision criterion are not reported in the registry record. Statistical interpretations beyond the stated summaries and planning assumptions would therefore be speculative.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies Cmax as the listed primary outcome and refers to both Cmax and AUC0-t in its definition of the pharmacokinetic set. It does not report how the two pharmacokinetic endpoints were prioritized for formal inference, whether one was primary and the other supportive, or whether any adjustment for multiple comparisons was planned. A multiplicity strategy is not reported in the registry record.

The registry reports a pharmacokinetic set of 36 subjects, each with one evaluable value for the reference product and one for the test product for the primary pharmacokinetic endpoints, without important protocol violations relevant to statistical evaluation. This describes the stated analysis population. It does not establish that the set includes everyone enrolled, nor does it explain the handling of participants without a complete pair of evaluable values.

Enrollment totals, reasons for exclusion, missing measurements, withdrawals, and the handling of missing data are not reported in the registry record. The record also does not describe whether any sensitivity analyses were conducted, or whether analysis populations other than the pharmacokinetic set were used for efficacy or safety summaries.

General: Multiplicity matters when several outcomes or comparisons are evaluated because repeated testing can affect the chance of false-positive findings. Missing-data methods matter because the result can depend on why observations are absent and how the analysis handles them. These are general considerations, not claims about procedures used in this study. Without a stated testing hierarchy, missing-data plan, or numerical results, neither the impact of multiplicity nor the effect of missingness can be assessed.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

The registry lists 36 participants at risk for serious adverse events in each group: Mucosolvan® Adult Syrup and Ambroxol Hydrochloride Soft Pastille. It records zero participants affected by serious adverse events in each group. For other adverse events, it likewise lists 36 at risk and zero affected in each group.

These are the counts recorded in the registry, not evidence that no adverse effects were possible or that the formulations have identical safety profiles. In general, observing zero events in a study does not establish that the underlying event risk is zero; interpretation depends on the amount and duration of observation and the completeness of reporting. Follow-up duration and adverse-event collection details are not reported in the registry record.

The death counts are not reported in the registry record. The serious-event figures should be read as recorded counts for the listed groups, not as a comprehensive safety assessment or as proof of equivalence between formulations.

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

This study addresses a pharmacokinetic question: how bioavailability of ambroxol hydrochloride soft pastilles compares with that of Mucosolvan® adult syrup in healthy participants. The registry identifies Cmax as the listed primary outcome, gives its measurement unit and summary type, and describes the pharmacokinetic set used for evaluation.

What the registry record does not establish is the observed size or direction of the comparison. No numerical Cmax result, treatment contrast, uncertainty interval, or p-value is reported. The record also does not provide numerical AUC0-t results, although that endpoint is mentioned in the pharmacokinetic-set description. Consequently, the relative exposure result and its precision cannot be determined from this record.

The crossover designation gives useful context, but sequence, allocation, and analysis details are incomplete. Allocation is not stated, and the registry cautions that the arms are not a like-for-like control comparison. These features limit how confidently a reader can interpret any comparison even if numerical estimates were available.

The safety entries record no serious or other adverse events among the 36 participants at risk in either group. Those counts do not prove absence of risk or equivalence, and deaths are not reported in the registry record. The study’s stated population is healthy; the record does not establish what the findings would mean for other populations.

In general, a study’s objective, endpoint definition, and analysis population are different from its result. The registry record documents the first elements but does not supply the numerical results needed to judge the comparative pharmacokinetic findings. It therefore supports a description of the question and reporting limitations, not a conclusion that one formulation produced higher, lower, or equivalent exposure.

13. Why This Trial Matters Statistically

This trial illustrates why a clearly stated objective and endpoint are only part of a statistical interpretation. The registry explains that the study compared two ambroxol hydrochloride formulations and identifies Cmax as the listed primary outcome. It also describes the pharmacokinetic population as participants with evaluable values for both products. These details clarify what the comparison was intended to address.

At the same time, the record does not include numerical pharmacokinetic results. Without an estimate and its uncertainty, readers cannot assess the direction, magnitude, or precision of the comparison. A design label or endpoint name cannot substitute for reported outcomes.

The study also highlights the importance of design transparency. A crossover model can offer within-participant comparisons in general, but interpretation depends on information such as treatment order, period structure, and analysis. Those details are not reported, and allocation is not stated. The registry additionally cautions that the arms are not a like-for-like control comparison. These qualifications matter when assessing what the design can support.

Finally, the defined pharmacokinetic set should not be confused with the total enrolled population. The record reports 36 subjects in that set but does not give enrollment totals or explain exclusions and missing data. The serious adverse-event counts are also limited: zero affected participants are recorded in each listed group, while deaths are not reported. Together, these features show why statistical reading depends on endpoint results, population flow, analysis methods, and transparent safety reporting—not only on the study’s stated purpose.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation for interpreting the pharmacokinetic findings is that numerical outcome results are not reported in the registry record. No Cmax estimates, contrast, confidence interval, or p-value is available, and AUC0-t results are not reported. The relative bioavailability findings therefore cannot be quantified or judged for precision.

Important design and analysis details are also missing. The record identifies a crossover model but does not report treatment sequence, period structure, washout, or handling of period or sequence effects. Allocation is not stated, and the registry cautions that the arms are not a like-for-like control comparison. The statistical test or model used is not reported.

The pharmacokinetic set is defined as 36 subjects with evaluable values for both formulations and without important protocol violations relevant to statistical evaluation. The total enrolled population, participant flow, exclusions, withdrawals, and missing-data handling are not reported. The record does not describe a multiplicity approach for the pharmacokinetic endpoints or provide the trial’s own sample-size justification.

Safety reporting is limited to the listed serious and other adverse-event counts. The death counts, follow-up duration, and detailed adverse-event collection procedures are not reported. The study population is described as healthy, so the registry record does not establish how findings might apply to other populations. These limitations concern what can be learned from the registry record; they do not determine what may have been reported elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Relative Bioavailability Study Between Two Formulations Containing Ambroxol Hydrochloride — NCT02572609.
• Registry record last updated 2015-12-31; status last verified 2015-11.
• Results first posted 2015-12-31.
• 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.

18. Record Summary

NCT02572609 is a completed phase 1 crossover study sponsored by Boehringer Ingelheim. It began in 2011-11 and reached primary completion in 2011-12. The study aimed to evaluate the bioavailability of ambroxol hydrochloride soft pastilles compared with Mucosolvan® adult syrup in healthy participants. Masking is listed as none.

The listed primary outcome is Cmax, measured in ng/mL and summarized using a geometric mean and geometric coefficient of variation. The pharmacokinetic set comprised 36 subjects with evaluable values for both formulations for the primary pharmacokinetic endpoints. Numerical pharmacokinetic results and key analysis details are not reported in the registry record.

The registry records zero serious and zero other adverse events among 36 participants at risk in each group. Death counts are not reported. Allocation is not stated, and the registry cautions that this is not a randomized, like-for-like control comparison.