Evaluation of Food Effect on the Pharmacokinetics of Sustained Release Metformin in Healthy Indian Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Food Effect on the Pharmacokinetics of Sustained Release Metformin in Healthy Indian Volunteers (NCT01561976), a randomized na study. The primary outcome is Maximum Observed Concentration (Cmax).

2. Clinical Question

3. Trial Design

The registry describes a randomized, single-center, open-label, single-dose, three-period, six-sequence crossover study. Thirty healthy adult volunteers were enrolled. In a crossover design, participants receive multiple conditions over successive periods, so each participant can contribute measurements under more than one condition. This can make within-participant comparisons informative because each participant serves as a reference for their own measurements, although the validity of that approach depends on appropriate conduct and analysis.

The three treatment conditions were 1000mg sustained-release metformin while fasting, 1000mg sustained-release metformin while fed, and a fed fixed-dose combination of sustained-release metformin 1000mg with glimepiride 2mg. The registry lists random allocation and no masking. The treatment comparisons therefore address both the food condition for the standalone metformin formulation and the fed combination against the fasting standalone formulation.

The primary outcome was Cmax, measured from blood samples collected before dosing and at the listed post-dose times through 30 hours. The posted arm estimates each include 24 participants. The registry does not report why this number differs from the enrollment of 30, or whether any participants were excluded from a particular analysis. The dates recorded for study start and primary completion are 2012-01-30 and 2012-02-21, and the study status is completed.

The study was designed to estimate pharmacokinetic exposure in healthy volunteers. It was not described as a trial of diabetes outcomes or as a comparison of clinical benefit. Further details of sequence assignment, period conduct, washout, and the handling of possible period or carryover effects 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: A total of 30 participants were enrolled in this study. METLEAD™ Forte SR (metformin hydrochloride prolonged release) and METLEAD™ G2 Forte (metformin hydrochloride sustained release/glimepiride) are registered product of GlaxoSmithKline.

Period 1

Reasons for not completing this period:

Washout Period 1 (7 Days)

Reasons for not completing this period:

Period 2

Washout Period 2 (7 Days)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Population included participants who received study medication. Only those participants available at the indicated time 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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Concentration (Cmax), measured over 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing.

The primary endpoint, maximum observed concentration (Cmax), is the highest measured concentration of metformin in blood after a dose. It is a measure of peak exposure. In this study, the registry specifies blood sampling at pre-dose and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing. Cmax depends on the concentrations observed at those sampling times; the recorded maximum is not necessarily the exact biological peak between samples.

Comparing Cmax across fed and fasting conditions can help characterize whether the observed peak concentration differs with food under the study conditions. The registry reports geometric means and geometric coefficients of variation for each treatment condition, and sponsor analyses express comparisons as ratios. A ratio is suited to comparing positive pharmacokinetic measurements on a relative scale. It should be interpreted as a comparison of peak exposure, not as a direct measure of clinical benefit or harm.

The primary endpoint description refers to a 90% confidence interval for the fed-to-fasting geometric-mean ratio. The posted analyses instead list 95% confidence intervals. This difference in the registry's descriptions should be kept in mind when reading the estimates.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover comparison estimate?

In a crossover study, each participant receives more than one treatment condition across different periods. Rather than relying only on differences between separate groups of participants, the analysis can compare a participant's measurements under different conditions. This approach can account for stable participant characteristics that affect concentration measurements. It also requires attention to how treatment sequence, period, and possible residual effects are handled. The registry identifies a randomized three-period, six-sequence crossover design, but the details of sequence allocation and the statistical treatment of period or carryover effects are not reported in the registry record.

The posted results give treatment-specific geometric means and sponsor estimates of ratios. A ratio expresses one treatment's estimated concentration relative to another treatment's estimate. A value of 100 is the ratio-scale reference for equal estimates. The reported fed-versus-fasting ratios are 108.94 for sustained-release metformin and 107.24 for the fed combination versus fasting sustained-release metformin. These values are reported by the registry; no additional numerical re-calculation is stated in the record.

Why use geometric means and ratios?

Pharmacokinetic measurements are positive quantities and can be unevenly distributed, with some observations farther from the center than others. A geometric mean summarizes measurements on a multiplicative scale and is commonly used for exposure comparisons. Ratios are natural on this scale: the analysis compares relative rather than absolute differences. The general statistical rationale is that transforming measurements to a logarithmic scale can make multiplicative comparisons suitable for standard model-based analysis; estimates can then be expressed back as ratios. This explanation is general, and the registry does not provide all details of the transformations or model specification.

The reported geometric coefficient of variation describes relative variability around the geometric mean. It is not the confidence interval for the mean and does not convey the precision of the treatment comparison by itself. The arm summaries list coefficients of 28.1, 26.13 and 27.16 for the fasting, fed and combination conditions, respectively. The registry does not specify further details of how these coefficients were calculated.

How should confidence intervals be read?

A confidence interval represents uncertainty in an estimated parameter under the model and sampling assumptions. A narrower interval indicates greater precision than a wider interval, all else being equal. For a ratio, 100 is the equal-estimate reference. The 95% interval reported for fed sustained-release metformin is 101.01 to 117.50; the interval for the fed combination comparison is 99.37 to 115.73. These intervals describe uncertainty in the estimated ratios, not the spread of individual Cmax values.

The primary endpoint description says a 90% confidence interval was constructed, whereas the posted sponsor analyses specify 95% confidence intervals. The record does not explain this difference. The stated confidence level matters because the interval's coverage convention is part of its interpretation, so readers should retain the confidence level attached to each reported result rather than treating the descriptions as interchangeable.

What does the ANOVA label tell the reader?

The sponsor analyses are labeled ANOVA, a general approach that compares modeled outcomes across conditions. In crossover pharmacokinetic studies, an analysis may account for repeated observations and design features, but the label alone does not specify which terms were included or how the model was fitted. The registry does not report the full model formula, assumptions checks, treatment of sequence or period, or the exact hypothesis associated with each p-value. Those details cannot be inferred from the method label alone.

The p-values listed for both comparisons are 0.141. A p-value describes how compatible the data are with a specified null hypothesis under the analysis assumptions; it is not the probability that a hypothesis is true, nor a measure of clinical importance. Because the registry does not state the tested null hypothesis in sufficient detail, the p-values should be reported as posted rather than assigned a more specific interpretation.

What do the planning assumptions mean?

The registry's planning illustration is described as using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers detecting a stated fraction of the observed effect. Such illustrations are prospective planning calculations, not observed power and not evidence that the trial was designed around those assumptions. The registry does not report the trial's own sample-size justification, and no conclusion about the actual design rationale can be drawn from the planning description.

In general, planning calculations depend on assumptions about the effect to detect, variability, allocation, and testing procedure. Choosing a smaller effect to detect generally requires more information for comparable precision. That general relationship does not reveal the study's intended target effect or whether its enrollment was adequate for a particular question. The registry does not report enough detail to reconstruct a protocol-based sample-size calculation.

What analysis details remain unavailable?

The registry states that the pharmacokinetic population included participants who received study medication and that only participants available at indicated time points were analyzed. It does not report the specific missing-data procedure, participant flow by period, reasons for unavailable observations, or whether any sensitivity analyses were performed. It also does not report interim analyses or a detailed multiplicity strategy. These omissions limit the ability to assess how robust the posted estimates are to analytical choices, especially across multiple outcomes and comparisons.

10. Analyses Reported by the Sponsor

The registry reports the sponsor's ANOVA comparisons directly: the ratio is 108.94 (95% confidence interval 101.01 to 117.50; p = 0.141) for fed sustained-release metformin versus fasting sustained-release metformin, and 107.24 (95% confidence interval 99.37 to 115.73; p = 0.141) for the fed combination versus fasting sustained-release metformin. The posted arm-level geometric means are also available, but no separate numerical recalculation of either ratio is reported in the registry record.

Accordingly, there is no independently reported recalculated estimate to set against the sponsor's analysis. The registry marks no discrepancy between the posted analyses and any recalculation. The sponsor's model-based estimates should be distinguished from the arm summaries: arm-level geometric means do not, by themselves, reproduce a crossover analysis that may account for within-participant structure and other model terms. The exact ANOVA specification is not reported, so the degree to which a simple calculation from the arm summaries would match the sponsor analysis cannot be established.

The registry's primary endpoint description specifies a 90% confidence interval, while the sponsor analyses list 95% confidence intervals. The record does not explain that difference. The posted analysis values and their stated confidence levels should therefore be read as recorded, without substituting an unreported recalculation.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome, maximum observed concentration, and six secondary outcomes: AUC from pre-dose to the last quantifiable concentration, Tmax, Tlag, Kel, terminal phase half-life, and counts of participants with adverse events and serious adverse events. It also reports two Cmax comparisons against the fasting sustained-release formulation. Testing multiple outcomes or comparisons can increase the chance of at least one apparently notable result when no adjustment is made. Whether and how to control that risk depends on the analysis plan and the role assigned to each outcome.

A multiplicity-adjustment strategy is not reported in the registry record. The record also does not report a prespecified hierarchy for interpreting primary and secondary endpoints, or how the two Cmax comparisons were handled as a family of tests. The two p-values are both listed as 0.141, but their presence alone does not establish whether they were adjusted or what exact null hypothesis each addresses.

The primary endpoint population is described as participants who received study medication, with only those available at indicated time points analyzed. Each posted Cmax arm estimate includes 24 participants, compared with 30 enrolled. The registry does not report the reasons for this difference, participant flow across the three periods, or the number with complete observations for each comparison. It does not specify whether missing measurements were imputed, omitted, or addressed through another procedure. The stated availability-based analysis suggests that availability at a time point mattered, but does not provide enough detail to determine the implications for missingness.

Interim analyses, data-monitoring procedures, and sensitivity analyses are not reported in the registry record. Without these details, the results can be described as posted but the extent to which alternative analysis choices might change the estimates cannot be assessed from the registry information alone.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events in each of the three treatment conditions. The number at risk for serious adverse events was 24 for fasting sustained-release metformin, 24 for fed sustained-release metformin, and 24 for the fed metformin–glimepiride combination. No deaths are listed.

For non-serious adverse events, the registry lists zero participants affected in the fasting condition, one in the fed sustained-release condition, and two in the fed combination condition; each condition lists 24 participants at risk. These are participant counts in the posted safety results. They should not be read as a comprehensive account of event type, timing, severity, or relationship to study medication. No serious adverse-event terms are listed.

The study involved a single dose in healthy volunteers and the reported counts are limited to the registry's listed safety data. Zero recorded serious events does not establish that serious events are impossible, and the small number of participants limits what these counts can characterize. The registry does not provide additional safety analysis details or a broader clinical safety assessment.

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

The results quantify observed metformin peak concentrations under three specific conditions in healthy volunteers: fasting sustained-release metformin, fed sustained-release metformin, and the fed sustained-release metformin–glimepiride combination. The sponsor reported ratio estimates and confidence intervals for the fed conditions compared with fasting sustained-release metformin. The reported intervals express uncertainty in those comparisons under the sponsor's analysis.

The findings do not answer whether either formulation improves diabetes outcomes, whether food changes tolerability in routine care, or whether one regimen is preferable for a particular person. The participants were healthy volunteers, the study was single-dose, and the primary endpoint was a pharmacokinetic measure. It did not assess long-term glucose control or clinical outcomes. No medical or treatment recommendation follows from these estimates alone.

The study also does not isolate every possible reason for a difference in concentration between the fed combination and fasting standalone metformin: those conditions differ in both food state and formulation composition. The standalone fed-versus-fasting comparison more directly addresses food condition for the metformin formulation, but remains specific to the study's dose, sampling schedule, and population.

Precision should be considered alongside the point estimates. The registry reports 95% intervals for the sponsor comparisons, while the endpoint description refers to 90% intervals. It does not give a detailed analysis plan, missing-data procedure, or sample-size justification. The conclusions supported by this record are therefore descriptive and pharmacokinetic: they concern the posted Cmax estimates and their reported uncertainty, not clinical effectiveness or outcomes beyond the trial conditions.

14. Why This Trial Matters Statistically

This study illustrates why pharmacokinetic questions require careful attention to both the treatment condition and the comparison being made. The trial includes a direct fasting-versus-fed comparison for sustained-release metformin, as well as a fed combination condition. These comparisons do not answer identical questions: the combination condition changes the formulation as well as including food, while the standalone comparison focuses on food condition within the metformin formulation.

The crossover design is also statistically relevant. Repeated measurements from the same participant can support a more informative comparison than unrelated groups when the analysis appropriately reflects the design. Yet a registry label such as ANOVA does not reveal how repeated observations, sequence, period, or potential carryover were modeled. The missing model details make the published numerical summaries easier to describe than to independently reconstruct.

The record shows another practical issue in reading trial results: endpoint descriptions and posted analyses can differ in their stated confidence level. The primary endpoint text refers to 90% confidence intervals, whereas the sponsor analyses report 95% intervals. Preserving that distinction avoids presenting uncertainty with a level not attached to the corresponding analysis.

Finally, the contrast between enrollment of 30 and 24 participants in each posted treatment summary highlights the importance of understanding analysis populations and participant flow. The record identifies an availability-based pharmacokinetic population but does not explain the difference. That is a meaningful limitation for readers assessing how completely the analyzed participants represent those enrolled.

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.

The registry provides limited information for assessing the full statistical conduct of the trial. Although it identifies a randomized, open-label, three-period, six-sequence crossover design, detailed sequence procedures, period handling, and possible carryover assessment are not reported in the registry record. The sponsor analyses are labeled ANOVA, but the model terms and assumptions are not described. This prevents independent evaluation of whether the analysis fully reflects the crossover structure.

The enrollment was 30, while each posted treatment estimate includes 24 participants. The registry states that only participants available at indicated time points were analyzed, but does not report why the analyzed count differs, how many participants completed each period, or how missing concentration observations were handled. These details matter for understanding whether the analyzed data could be affected by patterns of missingness.

The primary endpoint description calls for 90% confidence intervals, while the reported analyses give 95% intervals. The reason for the difference is not reported. The record also does not provide the trial's sample-size justification, detailed multiplicity plan, interim-analysis information, or sensitivity analyses. Planning illustrations are described as based on the observed effect and stated assumptions, but are not evidence of the original design rationale.

Finally, this was a single-dose pharmacokinetic study in healthy volunteers. The results address measured concentrations, not longer-term exposure, diabetes outcomes, or clinical effectiveness. Safety counts are limited, and the registry does not provide detailed event descriptions beyond the reported counts. These limits constrain how broadly the findings can be applied.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluation of Food Effect on the Pharmacokinetics of Sustained Release Metformin in Healthy Indian Volunteers — NCT01561976.
• Registry record last updated 2017-10-16; status last verified 2017-08.
• Results first posted 2017-10-16.
• 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.

19. Record Summary

NCT01561976 is a completed randomized, open-label crossover study of sustained-release metformin under fasting and fed conditions, with a fed metformin–glimepiride combination condition. The registry reports enrollment of 30 healthy adult volunteers and Cmax as the primary outcome. Each posted treatment estimate includes 24 participants.

The sponsor analyses report ratios of 108.94 for fed sustained-release metformin versus fasting sustained-release metformin and 107.24 for the fed combination versus fasting sustained-release metformin. Both analyses list p = 0.141; the respective 95% confidence intervals are 101.01 to 117.50 and 99.37 to 115.73. The endpoint description refers instead to 90% confidence intervals.

The registry lists zero serious adverse events and no deaths. It does not report the reasons for the difference between enrollment and analyzed counts, detailed model specifications, missing-data procedures, multiplicity methods, or the trial's own sample-size justification. The evidence recorded is pharmacokinetic and specific to single-dose conditions in healthy volunteers.