A Bioequivalence Study Comparing A Fixed Dose Combination Formulation, Rin 150 And Individual Reference Drugs In Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Bioequivalence Study Comparing A Fixed Dose Combination Formulation, Rin 150 And Individual Reference Drugs In Healthy Volunteers (NCT02014272), a randomized phase 1 study. The primary outcome is Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast).

2. Clinical Question

The study asked whether a fixed-dose tablet containing rifampicin and isoniazid had comparable pharmacokinetic exposure to the corresponding individual reference preparations after oral administration under fasting conditions. It enrolled healthy volunteers rather than people being treated for a disease. As a bioequivalence study, its focus was on comparing drug exposure, not on comparing clinical outcomes or treatment benefit.

The primary outcome is a pharmacokinetic measure, and the registry describes it for both rifampicin and isoniazid. It does not report a single overall result for the comparison, nor does the record give a numerical estimate or confidence interval that would establish how closely exposure matched. The relevant question is therefore identifiable from the study description, but the posted results do not allow the size or precision of the primary comparison to be assessed.

3. Trial Design

This was a phase 1, randomized, open-label, single-dose, two-way crossover study. It compared RIN 150 with individual reference preparations of rifampicin and isoniazid in healthy adults under fasting conditions. The study is marked completed. The registry lists enrollment of 28, a start date of 2012-09, and primary completion in 2012-10.

A crossover design means that participants receive more than one treatment condition in a planned order, allowing each participant's measurements under one treatment to be compared with their measurements under another. In general, this can reduce the influence of stable differences between participants. The record identifies the design as a crossover but does not report the treatment sequences, the interval between periods, or how period and sequence effects were handled. Those details should not be inferred from the design label alone.

Randomization was reported, and masking was reported as none. Thus, the record describes a randomized but open-label study. The treatment was a single oral dose, and the primary outcome was assessed through pharmacokinetic sampling on Day 1. The stated sampling schedule began before dosing and continued through 24 hours post-dose. The primary pharmacokinetic analysis set included treated participants with at least one estimated parameter of primary interest; further rules for inclusion or exclusion are not reported in the registry record.

The primary outcome was AUClast, reported for rifampicin and isoniazid. Secondary outcomes included area under the curve from time zero to extrapolated infinite time, plasma decay half-life, and time to maximum observed plasma concentration. The registry lists seven outcome measures and six analyses, but it does not report the full analysis plan or explain how outcomes and analyses correspond. The design description therefore establishes the broad comparison and measurement approach, while important operational and analytical details remain unavailable.

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.

Intervention Period 1

Reasons for not completing this period:

Washout Period 1 (7 Days)

Intervention Period 2

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.

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: Analysis population included all randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast), measured over 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1.

AUClast is the area under the plasma concentration-time curve from dosing to the last measured concentration. It represents cumulative measured drug exposure over the sampling period: concentrations are considered over time rather than treating a single blood concentration as the whole exposure profile. The registry reports this endpoint separately for rifampicin and isoniazid, in nanogram-hours per milliliter.

Pharmacokinetic exposure measures are used in bioequivalence studies because a comparison of concentration profiles can assess whether two formulations deliver similar amounts of a drug into the body over time. In general, the area under the curve captures overall exposure during the measured interval, while other pharmacokinetic measures can describe aspects such as the timing of peak concentration or the decline in concentration. These are general interpretations of the measures, not claims about the results of this trial.

The endpoint is specified over a schedule of plasma samples from pre-dose through 24 hours post-dose on Day 1. The registry identifies the reported summary as a geometric mean with geometric coefficient of variation as the dispersion measure. However, numerical AUClast values, a between-treatment estimate, and its uncertainty are not reported in the registry record. The endpoint definition alone does not establish whether the two preparations met a bioequivalence criterion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized crossover study and reports geometric means for the primary pharmacokinetic measure. Those labels indicate the broad statistical setting, but the specific model, comparison estimates, and uncertainty intervals are not reported in the registry record. The following concepts explain how such methods are generally interpreted without asserting which unreported procedures were used.

What does a crossover comparison do?

In a crossover study, participants receive multiple treatment conditions, and measurements can be compared within the same participant. In general, this can help account for stable participant characteristics because each participant contributes observations under both conditions. The benefit depends on appropriate treatment ordering and timing, and on accounting for possible period effects. A crossover is not automatically free of bias: treatment sequence, carryover, missed periods, and changes over time may matter. The registry identifies a randomized, two-way crossover design but does not report the sequences, washout interval, or analysis of period or sequence effects. Those aspects cannot be evaluated from the design label alone.

Why report a geometric mean?

Pharmacokinetic measurements such as area under the curve are often positive and may vary proportionally rather than by a fixed additive amount. In general, analysis on a logarithmic scale can be useful for this kind of data. A geometric mean summarizes the central value after accounting for multiplicative variation. When treatment comparisons are made on a log scale, results may be expressed as a ratio after transformation back to the original scale. That is a general explanation of common practice, not a statement that a specific ratio or model was reported for this trial. The registry gives no numerical comparative estimate.

The geometric coefficient of variation describes dispersion relative to a geometric mean. It should not be mistaken for the standard error or for a confidence interval. A confidence interval describes a range of values compatible with the data and analysis under the method's assumptions; it communicates uncertainty about an estimate. Neither a geometric coefficient of variation nor a treatment-specific geometric mean alone answers how precise the between-treatment comparison is. The registry does not report comparative confidence intervals for AUClast.

What does AUClast capture?

AUClast integrates measured plasma concentrations from dosing to the final quantifiable sample. In general, area under the curve is used as a summary of exposure across time, while a peak concentration focuses on the highest observed level. AUClast is bounded by the last quantifiable measurement and therefore differs conceptually from an area extrapolated to infinite time. The registry lists the latter as a secondary outcome, alongside half-life and time to maximum observed concentration. The primary sampling schedule runs from pre-dose through 24 hours post-dose on Day 1, with multiple intervening collection times. The endpoint definition makes the intended measurement clear, but no numerical values are reported.

How should uncertainty and bioequivalence be assessed?

For a bioequivalence question, the point estimate alone is generally not enough. The estimate's uncertainty and a prespecified acceptance range are important to judging whether the comparison is sufficiently precise and compatible with the intended standard. The registry record does not report the comparative estimate, its confidence interval, the acceptance limits, or the decision rule. Therefore, it is not possible to use the posted results to make a statistical bioequivalence determination. The study's name and stated purpose are not substitutes for those results.

What can be said about planning calculations?

Planning illustrations based on an observed effect answer a hypothetical question about the sample size associated with stated assumptions; they do not describe the trial's original design rationale. The assumptions stated for such illustrations are 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. These are planning assumptions, not evidence of the analysis that was conducted. Such calculations are not observed power and should not be treated as proof that the study was adequately or inadequately designed. The registry record does not report the original sample-size justification or its assumptions.

The analysis population is defined as treated participants with at least one estimated pharmacokinetic parameter of primary interest. This definition says which general group was eligible for the pharmacokinetic parameter analysis; it does not identify how many participants contributed to each endpoint, how missing concentrations were handled, or what exclusions occurred. Those details, as well as the specific statistical model and diagnostic checks, are not reported in the registry record. Statistical interpretation should remain limited to the method and results that are actually described.

10. Multiplicity, Missing Data and Analysis Populations

The record lists AUClast as the primary outcome for both rifampicin and isoniazid. It also lists secondary pharmacokinetic outcomes: area under the curve from time zero to extrapolated infinite time, plasma decay half-life, and time to maximum observed plasma concentration. In total, the registry lists seven outcome measures and six analyses. This indicates that more than one measure or analysis is part of the record, but the entries do not explain the full relationship among them.

Multiplicity arises when several outcomes, treatment comparisons, or analyses are considered. In general, examining multiple results can increase the chance of finding an apparently notable result by chance, depending on the analysis and decision process. The registry does not report whether multiplicity was addressed, how outcomes were prioritized beyond identifying AUClast as primary, or whether any adjustment or hierarchical testing plan was used. The statistical plan is not reported in the registry record, so no adjustment should be assumed.

The record defines the pharmacokinetic analysis set as treated participants with at least one estimated parameter of primary interest. It does not report the number included in each pharmacokinetic analysis, endpoint-specific missingness, reasons for missing data, or rules for handling measurements below quantification limits. It also does not report how incomplete crossover periods or unavailable samples were treated. These omissions limit assessment of the population underlying any result, even though no numerical primary results are posted.

Planning illustrations are distinct from the study's original design justification. The stated illustration assumptions include a two-sided significance level of 0.05, equal allocation, and a normal approximation; they do not establish the trial's prespecified statistical plan. The original sample-size justification, handling of multiplicity, missing-data procedures, and interim analyses are not reported in the registry record.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events by treatment group. In the RIN 150 group, 27 participants were at risk and 0 were listed as affected by a serious adverse event. In the rifampicin and isoniazid reference group, 27 participants were at risk and 0 were listed as affected by a serious adverse event. These are participant counts in the posted record, not a full description of event types or severity.

For other adverse events, the record lists 27 participants at risk and 27 affected in the RIN 150 group, and 27 at risk and 26 affected in the reference group. The registry does not provide event-level details in the serious-event listing, and no top serious-event terms are listed. Death counts are not reported in the registry record.

These counts should be read descriptively. They do not indicate how many distinct adverse-event terms occurred, how long participants were observed for safety, or whether events were judged related to treatment. The record does not provide a statistical comparison of safety outcomes. The counts also do not answer the primary pharmacokinetic question or establish bioequivalence.

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

The posted record establishes that the study was designed to compare pharmacokinetic exposure after RIN 150 and individual rifampicin and isoniazid reference preparations in healthy adults. It identifies AUClast as the primary endpoint and describes a randomized, open-label, single-dose crossover design under fasting conditions. This information explains the intended comparison and the type of evidence the study sought to collect.

It does not establish the result of that comparison. Numerical AUClast findings, treatment-comparison estimates, confidence intervals, and bioequivalence acceptance criteria are not reported in the registry record. Without those elements, readers cannot assess the size of the estimated difference, the precision of the estimate, or whether a prespecified bioequivalence standard was met. A study's stated objective is not itself evidence that the objective was achieved.

The listed safety counts provide a limited description of participants affected by serious and other adverse events in the two groups. They do not provide details about individual events, attribution, duration, or a statistical comparison. Nor do they fill the gap in the pharmacokinetic results. The record should not be read as proving either equivalence or a difference in safety.

Applicability is also limited by the study population and setting described in the record. Participants were healthy adults, and the study evaluated a single dose under fasting conditions. The record therefore does not directly describe outcomes in people with an illness, repeated dosing, or conditions other than those stated. This is a scope limitation of the evidence described, not a judgment about how the formulations perform in other settings.

In general, a sound interpretation of a bioequivalence comparison depends on the estimated treatment relationship, its uncertainty, the prespecified acceptance criteria, and the analysis methods. The registry supplies the study question and some design details, but not those elements of the result. The most defensible conclusion is that the registry record describes a bioequivalence study but does not report enough primary-result information to determine its statistical conclusion.

13. Why This Trial Matters Statistically

This study illustrates why the distinction between a stated objective and a reported result matters in clinical statistics. The record gives a recognizable bioequivalence question, names the pharmacokinetic endpoint, and identifies a randomized crossover structure. Those features help readers understand what was intended. Yet without the comparative estimate and its uncertainty, the central statistical question cannot be answered from the posted results.

The crossover design is statistically relevant because it can use within-participant comparisons, which in general may reduce the influence of stable differences between participants. At the same time, interpreting crossover data requires attention to treatment order, period effects, and carryover. The record names the design but does not report details needed to assess these components. A design label is informative, but it is not a substitute for a transparent analysis description.

The endpoint also matters. AUClast summarizes measured exposure over time, while the listed secondary measures describe different aspects of a concentration profile. Knowing which measure is primary helps frame interpretation, especially when several outcomes are listed. The registry identifies a primary measure but does not report how the multiple outcomes and analyses were handled statistically.

Finally, the study shows why safety counts and pharmacokinetic conclusions must be kept separate. Serious and other adverse-event counts provide descriptive information, whereas bioequivalence is assessed through pharmacokinetic comparisons and their precision against relevant criteria. One type of result cannot stand in for the other. The value of the registry entry is its description of the design and intended measurements; its statistical conclusions remain limited by the absence of numerical primary findings.

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 central limitation is that the registry record does not report numerical primary-outcome results. It gives the endpoint definition and summary type but not AUClast values for the treatments, a comparative estimate, or a confidence interval. It also does not report the decision criteria for bioequivalence. This prevents quantitative assessment of the primary question.

Several design and analysis details are not reported in the registry record. These include treatment sequences, the interval between treatment periods, the handling of possible period or carryover effects, the statistical model for the primary comparison, and endpoint-specific analysis counts. The number enrolled is reported as 28, but the pharmacokinetic analysis set's actual size is not stated. The reason for the 27 participants at risk in each adverse-event group is not reported, and those safety denominators should not be assumed to represent the number analyzed for pharmacokinetics.

The record identifies multiple outcome measures and analyses but does not describe a multiplicity strategy. It does not report procedures for missing data, unavailable samples, below-quantification measurements, or incomplete periods. It also does not report the original sample-size justification or interim analyses. These unknowns limit appraisal of the analysis plan and its implementation.

The study population and conditions are another boundary on interpretation: the record describes healthy adults, a single oral dose, and fasting conditions. It does not provide results in other populations or settings. The registry's safety information is also limited to participant counts, without detailed event terms or a reported statistical safety comparison. These are limitations of what the registry record makes available, rather than evidence that the study did or did not meet its objectives.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Bioequivalence Study Comparing A Fixed Dose Combination Formulation, Rin 150 And Individual Reference Drugs In Healthy Volunteers — NCT02014272.
• Registry record last updated 2014-07-16; status last verified 2014-06.
• Results first posted 2014-07-16.
• 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

The registry record describes a completed phase 1, randomized, open-label, single-dose, two-way crossover study in healthy adults under fasting conditions. It lists enrollment of 28 and compares RIN 150, containing 150 mg rifampicin and 75 mg isoniazid per tablet, with individual reference preparations of rifampicin and isoniazid.

The primary outcome is AUClast for rifampicin and isoniazid, summarized as a geometric mean with geometric coefficient of variation. Secondary outcomes include area under the curve to extrapolated infinite time, half-life, and time to maximum observed concentration. The pharmacokinetic analysis set is defined by treatment and availability of at least one primary parameter.

The posted record includes safety counts but does not report numerical primary-outcome estimates, comparative confidence intervals, bioequivalence criteria, or a statistical conclusion. Important details of the analysis plan, missing-data handling, and sample-size justification are also not reported in the registry record.