A Study to Assess the Bioequivalence of Dapagliflozin/Metformin XR Fixed-dose Combination Tablets in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Bioequivalence of Dapagliflozin/Metformin XR Fixed-dose Combination Tablets in Healthy Subjects (NCT02637037), a randomized phase 1 study. The primary outcome is Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, crossover phase 1 study of fixed-dose combination tablets in healthy subjects. A crossover design means participants receive more than one treatment condition at different times, so comparisons can be made within the same participant. This can reduce the influence of stable differences between participants, although interpretation still depends on the study’s conduct and analysis. The registry record does not report the treatment sequence, washout duration, or the allocation details beyond randomized allocation.

The two study parts assessed dapagliflozin/metformin XR 5/500 mg and 10/1000 mg. For each strength, the Mount Vernon test product and Humacao reference product were administered under fed and fasted conditions. The treatment descriptions specify single doses. The registry record lists 80 enrolled participants and gives the study status as completed. The recorded start date is 2015-12-21 and the primary completion date is 2016-04-07.

Masking was recorded as none. Thus, the registry describes an unmasked study; it does not report that participants or study staff were blinded to treatment. In pharmacokinetic comparisons, laboratory concentration measurements are central, but the registry record does not describe laboratory blinding or other safeguards against measurement or analysis bias.

The primary outcome concerns area under the plasma concentration-time curve, with concentrations sampled from pre-dose through 72 hours after dosing during each treatment period. The registry lists seven outcome measures and 24 analyses, but does not provide a single summarized test-versus-reference result. The detailed treatment sequence, planned statistical model, sample-size justification, and criteria used to declare bioequivalence are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Sequences 1, 2, 3 and 4 Part 1: ABCD, BADC, ABDC, BACD Part 2: EFGH, FEHG, EFHG, FEGH (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted; E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) A total of 80 subjects were randomized into the study

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

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 Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State, measured over Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period.

The primary endpoint is area under the plasma concentration-time curve (AUC) for dapagliflozin and metformin following administration of the two fixed-dose combination strengths under fed or fasted conditions. AUC represents the overall measured drug concentration in plasma over a specified period. It is used in pharmacokinetic comparisons because it describes systemic exposure across the sampling interval, rather than concentration at only one moment.

The registry describes the endpoint using geometric means and geometric coefficients of variation, with units of h*ng/mL. Concentrations were scheduled to be measured before dosing and at multiple post-dose times through 72 hours for each treatment period. The registry record does not report the numerical geometric means, variability estimates, test-to-reference comparisons, confidence intervals, or any conclusion for the primary endpoint.

For bioequivalence, the relevant question is whether exposure from the test product is sufficiently comparable with exposure from the reference product under the conditions being evaluated. In general, such an assessment uses a prespecified comparison and acceptance criteria. The registry record does not report the criteria or analysis used to make that determination. Therefore, the endpoint description alone does not establish whether the products met a bioequivalence standard.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is based on pharmacokinetic measurements: concentrations of dapagliflozin and metformin in plasma at scheduled times after dosing. AUC summarizes concentration over time. In general, this is useful when the question concerns overall systemic exposure, since a single concentration measurement may not reflect the full concentration-time profile. The registry specifies geometric means and geometric coefficients of variation, but it does not report the numerical outcome values.

Why use geometric summaries?

Pharmacokinetic measurements are often positive and may vary multiplicatively: a participant’s exposure can differ by a proportion rather than by a fixed additive amount. For such data, analysis may use a logarithmic scale and then express results as geometric summaries or ratios. In general, a geometric coefficient of variation describes relative spread on a multiplicative scale. The registry’s endpoint description names geometric summaries, but does not state the detailed transformation, model, or calculation used.

What does the crossover design contribute?

In a crossover study, participants receive multiple treatment conditions, allowing the comparison to use each participant as their own reference. In general, this can account for stable between-person differences in exposure. It does not remove all sources of uncertainty: treatment sequence, period effects, changes over time, and possible carryover can matter. The registry identifies a randomized crossover design, but sequence details, washout information, and the planned handling of period or carryover effects are not reported in the registry record.

How should a comparison be judged?

In general, a bioequivalence analysis compares exposure for a test product with exposure for a reference product and evaluates uncertainty against prespecified acceptance criteria. A confidence interval is an uncertainty interval for the estimated comparison under the analysis assumptions. A result can only be interpreted in relation to both the estimated comparison and the acceptance limits. Neither numerical comparisons nor confidence intervals nor acceptance criteria are reported in the registry record, so the endpoint description does not reveal whether the study met a bioequivalence standard.

What does variability mean?

Variation in measured exposure may reflect differences between participants, within-participant variation across periods, measurement variation, and other factors. Geometric coefficients of variation are one way to describe relative variability. In general, greater variability can make an estimate less precise, while a well-controlled paired design may help distinguish treatment differences from stable participant differences. The posted registry record does not give the variability estimates or enough analysis detail to assess their role in this study.

What can be inferred from the listed analyses?

The registry lists seven outcome measures and 24 analyses. These counts indicate that multiple outcomes or analysis entries were recorded, but they do not explain how the analyses were organized or which comparisons were designated as confirmatory. The primary outcome description covers AUC under fed or fasted conditions, and the record also lists secondary pharmacokinetic measures such as time to maximum plasma concentration, terminal half-life, apparent clearance, and apparent volume of distribution. Numerical results for these outcomes are not reported in the registry record.

Statistical methods such as mixed-effects models, analysis of variance, and confidence-interval construction are general tools used in crossover pharmacokinetic studies; the registry record does not state which method was used. It also does not report assumptions checks, outlier handling, or sensitivity analyses. These omissions limit the ability to reproduce or independently evaluate the primary comparison from the registry entry alone.

Sample-size calculations based on an observed effect are planning illustrations, not evidence about the number of participants needed before the trial began and not observed power. The registry record does not report the original sample-size justification, target precision, or assumptions used in planning. Without a prespecified planning rationale and the outcome estimates, the enrolled count cannot by itself establish whether the study was sufficiently precise for its intended bioequivalence assessment.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures and 24 analyses. The primary outcome is AUC under fed or fasted conditions, while the listed secondary outcomes include time to maximum plasma concentration, terminal half-life, apparent total body clearance, and apparent volume of distribution. Multiple strengths, food conditions, analytes, and pharmacokinetic measures create several possible comparisons. The registry record does not explain which analyses were confirmatory, how comparisons were prioritized, or whether any multiplicity adjustment was planned or used.

Multiplicity matters because repeated statistical testing can increase the chance of at least one apparently notable result when many comparisons are examined. In general, a prespecified testing strategy clarifies how evidence across multiple outcomes or conditions should be interpreted. The analysis hierarchy and any adjustment for multiplicity are not reported in the registry record. Numerical outcome results are also absent, so the role of individual comparisons cannot be evaluated.

The registry defines the primary pharmacokinetic analysis set as participants in the safety analysis set who had at least one primary pharmacokinetic parameter calculable for at least one analyte and no major protocol deviations thought to affect the pharmacokinetic analysis. This description gives an eligibility rule for the analysis population, but does not report how many participants were included in that set or how many contributed to each comparison.

Missing concentration measurements, incomplete treatment periods, and other missing data can affect pharmacokinetic analyses. The registry record does not report the extent of missing data, imputation procedures, exclusions beyond the stated population definition, or sensitivity analyses. It also does not provide a participant flow description that would show how enrollment related to the analysis population.

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.

Most frequent non-serious adverse event terms

The safety entries list serious adverse events for each of the eight treatment conditions. The number affected is recorded as 0 in every entry. The number at risk ranges from 36 to 40 across those entries. These are treatment-entry counts in a crossover study, so participants may contribute to more than one treatment condition; the entries should not be added to estimate a count of unique participants.

Other adverse events are recorded for 2 participants in Treatment A, 5 in Treatment B, 1 in Treatment C, 2 in Treatment D, 2 in Treatment E, 4 in Treatment F, 4 in Treatment G, and 3 in Treatment H. The corresponding numbers at risk are 40, 38, 37, 36, 39, 40, 39, and 39, respectively. The registry does not provide event descriptions in the listed serious-event terms, and the serious-event term list is empty.

The death fields are null; death counts are not reported in the registry record. These safety counts are descriptive and do not establish a comparative safety effect. The record does not provide details needed to assess event severity beyond the serious-event classification, timing, relationship to treatment, or statistical comparisons.

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

This trial addresses a focused pharmacokinetic question: whether two strengths of a dapagliflozin/metformin XR fixed-dose combination made at one plant had comparable exposure to the corresponding product made at another plant, under fed and fasted conditions. A randomized crossover design and the use of AUC are consistent with evaluating that kind of comparison. The registry record does not report the numerical comparisons needed to answer the question.

It is therefore not possible to determine from the record whether the test and reference products met bioequivalence criteria. No conclusion about equivalence, difference, or the precision of the comparison can be drawn without the outcome estimates, confidence intervals, and criteria. The description of the objective is not a report of the result.

Likewise, the recorded serious-event counts do not establish that the products have the same safety profile. The entries show zero participants affected by serious adverse events in each treatment condition, alongside counts of other adverse events. The record does not report deaths as numerical counts or provide detailed event-level context. These observations should be read as limited descriptive safety information, not as a definitive comparative safety analysis.

The findings also apply to the study setting and population described: healthy male and female subjects receiving single doses of the specified formulations and strengths under the recorded food conditions. The record does not establish how pharmacokinetic or safety findings would apply to people with health conditions, to other dosing regimens, or to other formulations. More importantly, it does not provide the primary results needed even to characterize the test-versus-reference exposure comparison in this study.

The registry entry is consequently informative about the intended design and measurements, but incomplete as a report of the principal result. It does not support a claim that the test product is or is not bioequivalent to the reference product.

13. Why This Trial Matters Statistically

Bioequivalence studies ask a specific question about exposure: whether a test formulation and a reference formulation produce sufficiently comparable pharmacokinetic profiles under the conditions studied. This question differs from a trial designed to compare clinical outcomes. In this study, the products were fixed-dose combinations of dapagliflozin and metformin XR, and the comparison covered two strengths, two manufacturing plants, and fed and fasted conditions.

The randomized crossover design is statistically relevant because participants receive multiple treatment conditions, allowing within-participant comparisons. In general, this can reduce the influence of stable differences between participants. The design also makes the sequence and period structure important, which is why details of treatment order, washout, and analysis methods help readers assess a bioequivalence result. Those details are not reported in the registry record.

The registry identifies AUC as the primary endpoint and describes geometric summaries. These choices focus attention on overall measured exposure and relative variation. The record also lists other pharmacokinetic measures, which may add context about the concentration-time profile. However, the record does not report numerical estimates, uncertainty intervals, or acceptance criteria. Thus the statistical question is clear, but its answer cannot be recovered from the registry entry.

The study also illustrates why a completed status and a stated objective are not substitutes for reported outcome results. Enrollment and design details describe what was undertaken; they do not show whether the primary comparison was precise or met a bioequivalence standard. For statistical interpretation, the estimates and uncertainty are essential.

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 main limitation for interpreting this record is the absence of numerical primary pharmacokinetic results. The registry describes AUC and the analysis population, but does not report geometric means, test-to-reference estimates, confidence intervals, or a conclusion about bioequivalence. Without these, neither the direction nor precision of the comparison can be assessed.

Important analysis details are also not reported in the registry record. These include the statistical model, the acceptance criteria for bioequivalence, handling of period or sequence effects, treatment order, and any washout details. The record does not report the original sample-size justification, missing-data handling, or sensitivity analyses. These omissions limit reproducibility and independent evaluation.

The registry lists seven outcome measures and 24 analyses, but does not describe the analysis hierarchy or any strategy for multiplicity. That leaves uncertainty about how the different strengths, food conditions, analytes, and outcomes were interpreted together. The number of participants contributing to each pharmacokinetic comparison is not reported, despite the overall enrollment figure and the stated analysis-set definition.

Safety information is limited to treatment-entry counts. Serious adverse events are recorded as affecting 0 participants in each entry, while other adverse events are listed without descriptions in the record. Death counts are not reported in the registry record. The crossover setting also means treatment-entry participant counts should not be treated as counts of distinct individuals across the whole study.

Finally, the population consisted of healthy subjects and the listed regimens were single doses. The record does not establish applicability to other populations or dosing situations. These limitations concern what can be concluded from the registry record, not necessarily what may have been reported elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Assess the Bioequivalence of Dapagliflozin/Metformin XR Fixed-dose Combination Tablets in Healthy Subjects — NCT02637037.
• Registry record last updated 2018-03-13; status last verified 2018-03.
• Results first posted 2018-03-13.
• 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

NCT02637037 is a completed randomized, unmasked, phase 1 crossover study sponsored by AstraZeneca. It enrolled 80 healthy male and female subjects and compared dapagliflozin/metformin XR fixed-dose combination tablets manufactured at Mount Vernon with reference tablets manufactured at Humacao.

The study assessed 5/500 mg and 10/1000 mg strengths under fed and fasted conditions. The primary outcome was AUC for dapagliflozin and metformin, described using geometric means and geometric coefficients of variation. The primary pharmacokinetic analysis population is defined in the registry record.

The record lists seven outcome measures and 24 analyses. It reports treatment-entry safety counts, but does not report numerical primary outcome results, the analysis criteria for bioequivalence, or a conclusion about whether bioequivalence was established.