Genetic Basis for Variation in the Renal Elimination of Metformin: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Genetic Basis for Variation in the Renal Elimination of Metformin (NCT00187720), a non-randomized phase 4 study. The primary outcome is Renal Clearance of Metformin.

2. Clinical Question

3. Trial Design

This is a completed Phase 4 study with non-randomized allocation, no masking, and a parallel-group model. The registry lists an enrollment of 23. The groups are defined by OCT2 genotype: the OCT2-reference Group and the OCT2-variant Group. Each group was to receive a single oral dose of 850 mg of metformin. The study was sponsored by the University of California, San Francisco.

The registry describes the project as part of a larger multi-investigator grant investigating pharmacogenetics of membrane transporters. Its specific hypothesis was that genetic variation in hOCT2 is associated with variation in renal clearance of metformin. The primary-outcome description focuses on renal clearance among individuals homozygous for the reference OCT2 genotype and individuals carrying the A270S variant allele. This is an observational genotype-group contrast within a drug administration study, not an allocation of different treatments.

The study start is recorded as 2002-05 and primary completion as 2008-04. Its status is completed. The record lists one outcome measure and no analyses. Although the outcome definition and intended comparison are described, numerical outcome results and a statistical comparison are not reported in the registry record.

The non-randomized design matters for interpretation. Genotype defines group membership, and the registry states that the arms are not a like-for-like control comparison. Group differences, if reported, would be associations in this study population rather than randomized evidence that genotype alone caused a clearance difference. The record does not report masking or randomization beyond stating that masking was none and allocation was non-randomized, nor does it provide additional design details.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Analysis was per protocol. The sample size of 23 subjects will enable us to detect a significant difference (at the p \< 0.05 level; α = 0.05, β = 0.80) in the renal clearance of metformin between individuals who are homozygous for the reference OCT2 and those who carry the OCT2 variant A270S allele.

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 Renal Clearance of Metformin, measured over 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours.

The primary endpoint is renal clearance of metformin, expressed in mL/min. Renal clearance describes how efficiently a substance is removed from the circulation through the kidneys, represented as a clearance rate. The outcome is continuous, and the registry identifies the intended summary as a mean with standard deviation.

The study uses this endpoint to address its pharmacogenetic question: whether variation in OCT2 genotype is associated with variation in the renal elimination of metformin. The registry states that clearance is to be measured over time points at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours. It describes comparing the reference and variant groups, rather than comparing alternative metformin regimens.

In general, a clearance measure is relevant to a question about renal elimination because it quantifies removal through the kidney. A continuous endpoint can be summarized by a mean and standard deviation, which describe its average level and spread. Those summaries alone would not establish whether a between-group difference is statistically distinguishable from chance; an estimate of the contrast and its uncertainty would also be needed. The registry record does not report numerical endpoint values, group means, standard deviations, or a between-group estimate, so the magnitude and precision of any difference cannot be assessed from the reported results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a continuous measure summarized in the registry as a mean with standard deviation. The record identifies renal clearance in mL/min as the measure and specifies a series of measurement times from 0 through 24 hours. It does not report the resulting measurements or explain how measurements across those times were combined or analyzed. The endpoint description indicates the intended contrast between reference and variant genotype groups, but the registry record does not report an estimate of that contrast.

What does a mean and standard deviation describe?

In general, a mean describes the central level of a continuous measurement, while a standard deviation describes how spread out individual measurements are around that mean. These summaries are not interchangeable: two groups can have similar means but different spreads, or different means with substantial overlap in individual measurements. The registry identifies mean and standard deviation as the summary format, but numerical values for either group are not reported in the registry record. Thus, neither the average clearance nor its observed variability can be evaluated from the record.

How should a confidence interval be understood?

In general, a confidence interval expresses uncertainty around an estimated quantity, such as a group difference. A narrower interval indicates greater precision under the method used; a wider interval indicates less precision. It also communicates which effect sizes remain compatible with the observed data under the stated approach. No confidence interval for renal clearance is reported in the registry record. Without an estimate and its interval, the magnitude and precision of a possible genotype-group contrast cannot be assessed.

What does the stated significance threshold mean?

The registry describes a planned criterion of p < 0.05, with α = 0.05 and β = 0.80. In general, a significance threshold is a rule for judging whether data are sufficiently incompatible with a specified null hypothesis under an analysis model. It does not measure the size or importance of an effect. Beta is used in planning to describe the chance of failing to detect an effect of a particular assumed size; its meaning depends on the effect and variability assumptions used in the design. Those assumptions are not reported in the registry record. No endpoint p-value is reported, so the planned criterion cannot be used to infer the study result.

The record also describes the sample size of 23 subjects as enabling detection of a significant difference between the genotype groups. This should be read as a planning statement, not as an observed finding or a measure of the study's actual power after completion. The registry does not provide the effect size, variability, or other assumptions behind that statement. A separate planning illustration is described as based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. The illustration's numeric outputs are not reported in the registry record. Planning sample sizes are not observed power and do not substitute for the outcome estimate or its uncertainty.

Why does non-randomized allocation matter?

In general, randomization helps balance measured and unmeasured characteristics across treatment groups, on average, by assigning treatment independently of participant characteristics. This study instead compares genotype-defined groups and is recorded as non-randomized. The registry itself warns that the arms are not a like-for-like control comparison. Genotype group is therefore not a randomized treatment assignment. A difference in clearance could be associated with genotype, but causal attribution requires care, particularly if other characteristics differ between groups. The registry does not report adjusted analyses or information sufficient to evaluate such potential differences.

Masking is listed as none. In general, masking is intended to limit knowledge of group assignment from influencing conduct or assessment, depending on the study design. The registry does not describe additional procedures to reduce measurement or analysis bias. No inferential analysis, model specification, covariate adjustment, or method for repeated measurements is reported in the registry record. These omissions limit the ability to assess how the intended comparison would be estimated.

How should repeated measurements be considered?

The listed time points indicate repeated measurement over the dosing period. In general, measurements taken from the same person are related, so an analysis of the full time course would need to account for that within-person relationship if it modeled all observations together. Treating repeated observations as independent when they are correlated can misstate uncertainty. The record does not report whether the analysis used individual time points, a summary across time, or a repeated-measures model. It also does not identify a primary time point or an approach for handling observations that were not available.

The registry describes the analysis population as per protocol. In general, a per-protocol analysis includes participants who meet protocol-defined requirements, but the details depend on the protocol and its rules. Those rules, the number analyzed, and exclusions from analysis are not reported in the registry record. Enrollment alone does not establish how many participants contributed to the primary endpoint.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("OCT2-variant Group", "OCT2-reference Group")
n   <- c(9, 14)
m   <- c(614, 441)
sp  <- c(158, 108)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  OCT2-variant Group  9  614.000  158.000  492.550  735.450
CARM  OCT2-reference Group  14  441.000  108.000  378.643  503.357

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure, renal clearance of metformin, but the endpoint is measured at multiple scheduled time points: 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours. The record does not state whether each time point was analyzed separately, whether a single summary across time was used, or whether one time point was designated as primary for inference. It also does not report an adjustment for multiple comparisons. In general, testing multiple outcomes or time points can increase the chance of a false-positive finding if no multiplicity strategy is used; whether that concern applies depends on the actual analysis plan, which is not reported in the registry record.

The registry describes the outcome analysis as per protocol, but does not define the protocol criteria, report the analysis population size, or explain how participants were included or excluded. It does not report the extent of missing primary-outcome measurements, reasons for missingness, or any method used to address missing data. The record therefore does not permit assessment of whether missing observations could have affected the result.

The study lists one outcome measure and no analyses. Numerical primary-outcome results, an analysis population count, and statistical inference are not reported in the registry record. The record also does not report an analysis plan, interim analyses, or a correction for multiple testing. These absences mean that the intended analysis cannot be reconstructed in detail and that the robustness of any primary-outcome estimate cannot be evaluated from the registry entry.

12. 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 adverse-event record lists 14 people at risk in the OCT2-reference Group and 9 people at risk in the OCT2-variant Group. It records zero serious adverse events in each group and zero other adverse events in each group. These are counts in the registry record; they are not a comparison of randomized treatment arms, since both groups received metformin and allocation was non-randomized.

Zero recorded events should be read as no events listed for these categories in the registry entry, not as proof that the risk was absent. In general, an event count is most informative when accompanied by clear definitions, systematic collection methods, follow-up duration, and information about completeness of reporting. Those details are not reported in the registry record. The record does not provide a serious-event term list, and deaths are not reported in the registry record.

The at-risk counts are not a substitute for the primary endpoint results. They do not indicate renal clearance, nor do they establish whether the genotype groups differed on safety outcomes. Because the study is small and non-randomized, the listed counts should be interpreted descriptively rather than as evidence of comparative safety.

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

The record identifies a pharmacogenetic question: whether OCT2 genotype variation is associated with renal clearance of metformin. It describes a single oral dose of 850 mg in both genotype groups and a primary endpoint of renal clearance in mL/min, measured at scheduled times through 24 hours. Those details establish what the study set out to examine.

The record does not report numerical clearance results, group summaries, an estimated difference, a confidence interval, or a p-value. It therefore does not show whether clearance was higher or lower in either group, whether any observed difference was large or small, or how precisely the comparison was estimated. The completed status and planned sample-size statement do not fill this gap.

Even if a group contrast were reported, the design would remain non-randomized. Genotype-defined groups can support an association analysis, but they are not equivalent to groups created by randomized treatment assignment. The registry's caution that the arms are not a like-for-like control comparison should remain central to interpretation. The record does not report adjusted analyses that could address other differences between groups.

The registry entry also does not establish whether the scheduled repeated measurements were analyzed separately or combined, how missing measurements were handled, or what protocol rules defined the per-protocol population. These missing details limit assessment of the analysis as well as the result. The appropriate conclusion from this record is therefore about the scope of the research question and the limits of the reported evidence, not about the direction or clinical importance of a genotype-related clearance difference.

The safety counts list no serious or other adverse events in the recorded group summaries, but they do not establish absence of risk. The record supplies neither detailed event definitions nor information about completeness of collection. Safety counts and the unreported primary endpoint answer different questions and should not be treated as substitutes for one another.

14. Why This Trial Matters Statistically

This study is statistically notable because its comparison is defined by genotype rather than randomized intervention. Both groups received the same single oral metformin dose, while group membership reflects OCT2 genotype. This makes the target an association between genotype and renal clearance, not an estimate of the effect of assigning one treatment rather than another. Clear separation of those questions helps prevent an observational contrast from being interpreted as a randomized causal effect.

The outcome is continuous and is measured across a series of times. That structure raises important analysis questions: whether clearance is summarized at a particular time, whether measurements are combined, and how within-person dependence is handled. The registry record names the endpoint and schedule but does not report the analysis approach. For readers, this illustrates why a measurement schedule alone cannot identify the statistical model or determine how uncertainty was calculated.

The entry also distinguishes a design-stage sample-size statement from a completed-study result. It says that enrollment of 23 subjects was intended to enable detection of a significant difference under stated threshold and beta values, but does not report the assumptions behind that claim or the outcome estimate. A planned ability to detect an assumed effect does not demonstrate that the effect occurred. Nor can it replace reporting an estimate and its precision.

Finally, the record illustrates the importance of complete outcome reporting. The research question, genotype groups, dose, and endpoint are described, yet numerical primary-outcome results and analyses are not reported. Without those elements, readers cannot judge direction, magnitude, or uncertainty. The statistical value of a registry record depends not only on its design description but also on accessible results and transparent methods.

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 main limitation for interpretation is that the registry record does not report numerical results for its primary endpoint. There are no group means or standard deviations, between-group estimate, confidence interval, or p-value. The direction and magnitude of any renal-clearance contrast therefore cannot be assessed, and its precision is unknown.

The study enrolled 23 subjects and used non-randomized, genotype-defined groups. The registry states that the arms are not a like-for-like control comparison. The record does not provide participant characteristics that would allow assessment of group comparability or report adjusted analyses. As a result, any possible group difference could not be interpreted as an isolated causal effect of genotype on the basis of this entry alone.

The scheduled measurements extend across multiple times, but the record does not explain which measurements contributed to the primary analysis or how repeated observations were handled. It does not report a statistical model, covariate strategy, multiplicity approach, or method for missing measurements. Although the analysis is described as per protocol, the eligibility rules for that analysis and the number contributing to the endpoint are not reported.

The sample-size statement gives a significance threshold and beta value but does not state the effect-size or variability assumptions used. The separate planning illustration is described in general terms, but its numerical outputs are not reported in the registry record. These planning details cannot compensate for missing results. The study is recorded as completed, but completion does not establish that all planned measurements were available or that the primary analysis was reported.

Safety reporting is also limited: the entry lists zero serious and other adverse events in the group summaries, but does not report further collection details, and deaths are not reported in the registry record. These limitations are specific to what this record documents and constrain both efficacy-related statistical interpretation and assessment of safety reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Genetic Basis for Variation in the Renal Elimination of Metformin — NCT00187720.
• Registry record last updated 2013-01-10; status last verified 2012-12.
• Results first posted 2013-01-10.
• 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

The registry describes a completed Phase 4, non-randomized, unmasked, parallel study sponsored by the University of California, San Francisco, with enrollment of 23. It investigated whether OCT2 genetic variation was associated with renal clearance of metformin. The OCT2-reference and OCT2-variant groups were each assigned a single oral dose of 850 mg, and renal clearance was the primary endpoint, measured at scheduled times through 24 hours.

The registry identifies a per-protocol analysis and describes a sample-size aim using p < 0.05, α = 0.05 and β = 0.80. It lists one outcome measure and no analyses. Numerical primary-outcome results and details of the statistical analysis are not reported in the registry record. The adverse-event summary lists zero serious and other adverse events in both groups; deaths are not reported in the registry record.