Metformin Pharmacology in Human Cancers: A Proof of Principle Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Metformin Pharmacology in Human Cancers: A Proof of Principle Study (NCT03477162), a na early/phase 1 study. The primary outcome is Lung Tumor Tissue Concentration of Metformin.

2. Clinical Question

3. Trial Design

This was an early-phase 1, presurgical proof-of-principle study of metformin pharmacology in human cancers. Its stated aim was to determine steady-state concentrations of metformin in tissue and plasma in patients with surgically resectable thoracic tumors. The record identifies Dartmouth-Hitchcock Medical Center as the sponsor. Enrollment is listed as 18, and the study status is terminated. The record lists a start date of 2018-05-15 and a primary completion date of 2021-11-30; it does not state why the study was terminated.

The design is listed as single group, with allocation NA and masking none. Patients in the metformin arm were to receive the drug orally before surgery. The regimen is described as 750 mg QD for 4 days followed by 750 mg BID for 3-6 days, or clinically indicated metformin, for a total of 7-10 days up to the night before surgery. The intervention description and the primary outcome description both concern metformin, with the latter specifying extended release.

The primary outcome was lung tumor tissue concentration of metformin, reported by the registry as a median with full range, within 7 days from surgery. The registry also lists concentrations in adipose tissue, tumor-adjacent normal tissue, plasma, and whole blood as secondary outcomes. Controls are mentioned in the primary outcome description, but they did not receive metformin and were excluded from that analysis. A separate control group in the adverse-event record does not make this a randomized or like-for-like comparison. The statistical plan, eligibility detail beyond the described surgical population, and reasons for termination 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Controls do not receive Metformin and are not included in this analysis.

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 Lung Tumor Tissue Concentration of Metformin, measured over Within 7 days from surgery.

The primary endpoint is the concentration of metformin in lung tumor tissue, with units of ng/g and a measurement timeframe within 7 days from surgery. It is a pharmacologic endpoint: it concerns whether and at what level the study drug is present in the tumor tissue after presurgical dosing. It does not directly measure tumor response, survival, or another clinical outcome.

The registry specifies the median and full range as the summary for this endpoint. A median describes the middle observation in an ordered set and is less affected by extreme values than a mean; the full range conveys the span from the smallest to the largest observed value. These are general statistical properties. The endpoint description also states a goal of determining intra-tumor concentrations with a standard deviation no greater than 25% of the mean. That statement describes a precision target, but the registry does not provide the observed concentration, standard deviation, mean, or an explanation of how that target was assessed.

The pharmacologic question is relevant to a presurgical proof-of-principle design because tissue can be collected in connection with surgery. The record also lists concentrations in adipose tissue, tumor-adjacent normal tissue, plasma, and whole blood as secondary outcomes. Numerical results for the primary endpoint are not reported in the registry record, so the endpoint’s observed level and precision cannot be assessed from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design and endpoints call for a distinction between descriptive pharmacology and comparative treatment analysis. The main outcome concerns a measured concentration in lung tumor tissue after metformin administration. It is not an outcome framed as a difference between randomized groups. The registry labels the study single group and allocation NA, and says that controls do not contribute to the primary analysis. These design features matter because a group contrast requires comparable groups and a defined contrast; the record does not describe such a primary comparison.

What does the endpoint summary mean?

The primary endpoint is specified as a median with full range, in ng/g, within 7 days from surgery. In general, the median is the central observation after values are ordered. The full range reports the endpoints of the observed values and gives a simple description of their spread, though it does not show the pattern of values between those endpoints. The registry’s endpoint description also refers to a standard deviation no greater than 25% of the mean. Standard deviation is a measure of dispersion around the mean. The record does not explain how that precision target relates to the specified median-and-range summary or how it was assessed. No observed summary values are reported.

What can be inferred from the design?

A single-group pharmacology study can describe measured concentrations among participants who received the intervention, provided those measurements and the analysis population are reported. It cannot, by itself, separate a drug-related change from other explanations using a randomized control contrast. Here, the registry also mentions a control group in the safety record, but says the controls did not receive metformin and were not included in the primary outcome analysis. The registry cautions that the arms are not a like-for-like control comparison. The listed control data therefore should not be treated as a valid comparator for the tumor concentration endpoint.

In general, over-dispersion means that observed variation is greater than a model assumes. When that occurs, uncertainty estimates based on the less variable model can be too narrow, and tests can be poorly calibrated. The registry does not report a model for the concentration outcome, a dispersion assessment, or a statistical analysis plan, so no particular modeling approach or variance assumption can be attributed to this study.

What do the planning assumptions represent?

The record describes sample-size illustrations as planning calculations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect; for time-to-event calculations, the quantity is total events, while other calculations are participants per arm. These are planning illustrations, not the study’s own design justification and not observed power. The registry does not report a trial-specific sample-size justification, and no illustration results are stated in the registry record. No sample-size conclusion can be inferred from the assumptions alone.

In general, a significance level sets a threshold for a statistical test under its assumptions; it does not measure the size or practical importance of an effect. Equal allocation is an assumption of the stated planning illustrations, not evidence that the study enrolled equal numbers in comparable groups. The study itself is listed as single group, and the record cautions against treating the arms as a like-for-like control comparison.

What analyses are documented?

The record lists zero analyses. It does not report a statistical plan, hypothesis tests, confidence intervals, missing-data procedures, or adjustments for multiple outcomes. Six outcome measures are listed overall, and the named secondary outcomes include concentrations in adipose tissue, tumor-adjacent normal tissue, plasma, and whole blood. The record does not provide numerical results for those measures. In general, multiple outcomes can raise the chance of at least one apparently unusual finding when many tests are conducted; adjustment methods and prespecified outcome priorities can help address that issue. No multiplicity approach is reported, so none should be assumed.

The absence of analyses in the registry record limits interpretation; it is not evidence that no analyses were performed outside the posted record. Likewise, the enrollment figure does not identify how many participants had usable measurements for each endpoint. Analysis populations and endpoint-specific denominators are not reported in the registry record. Without those details and the numerical endpoint results, statistical precision and the robustness of any estimate cannot be assessed.

10. Multiplicity, Missing Data and Analysis Populations

The record lists six outcome measures overall and names secondary concentration outcomes in adipose tissue, tumor-adjacent normal tissue, plasma, and whole blood. It does not report a multiplicity strategy, such as a hierarchy of outcomes or an adjustment for multiple statistical tests. In general, when several outcomes are examined, the chance of finding at least one apparently notable result can increase; planned prioritization and suitable adjustment can help manage that issue. Because no analyses are listed, the registry record does not establish which outcomes were tested or how their results were interpreted.

Missing-data procedures are not reported in the registry record. The record gives enrollment as 18 but does not specify the number of participants with usable tumor tissue, the number contributing to each secondary outcome, or how unavailable measurements were handled. It also does not describe exclusions, withdrawals, or a method for imputing missing values. Those details are needed to understand whether reported summaries, if available, represent all enrolled participants or a subset.

The primary outcome description explicitly excludes controls. Beyond that statement, analysis populations are not described. The study is listed as single group, and the control arm in the safety record is not identified as a like-for-like comparator. No intention-to-treat or per-protocol population is specified. The record lists zero analyses, so no analysis population or missing-data method can be confirmed from posted results.

11. 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 adverse-event record lists 14 participants at risk in the Metformin group and 1 in the Control group for the displayed safety summaries. Serious adverse events are recorded for 0 in each group. The record lists 1 other adverse event in the Metformin group and 0 in the Control group. Deaths are recorded as 0 in both groups. These are counts in the registry’s safety record and should be read alongside the stated at-risk counts, not as estimates of comparative risk.

The groups are highly unequal in the posted safety counts, and the registry cautions that the arms are not a like-for-like control comparison. The record does not explain why these at-risk counts differ from the overall enrollment figure, or provide details on event definitions, observation time, severity grading, or causal attribution. The number of reported events alone cannot establish whether an event was caused by metformin. The absence of a recorded serious adverse event in these counts should not be interpreted as proof that no serious events could occur. The registry does not report a safety analysis or comparative statistical test.

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

This record addresses a presurgical pharmacology question: whether metformin concentrations could be measured in lung tumor tissue after short-term administration before surgery. The primary endpoint is a tissue concentration, not a measure of tumor shrinkage, survival, symptom change, or another clinical outcome. The record also lists concentration outcomes in other tissues and blood compartments, but does not report their numerical results.

The registry describes a median and full range for the primary concentration endpoint and states a precision goal involving the standard deviation and mean. However, it does not report the observed median, range, mean, standard deviation, or a confidence interval. The extent of observed variation and the precision of any estimate therefore cannot be evaluated. No clinical threshold or interpretation of a concentration is reported in the registry record.

The design is listed as single group. Controls are mentioned but excluded from the primary analysis, and the record cautions that the arms are not a like-for-like comparison. Thus, the posted information does not support a causal comparison between metformin and control. Nor does it provide a clinical efficacy conclusion. General pharmacologic measurements may help characterize drug presence in tissue, but interpreting their clinical significance requires evidence and context beyond the concentration endpoint reported in this record.

The study is marked terminated, but the reason is not reported in the registry record. Termination does not by itself explain whether the study achieved its pharmacologic objective, whether data were collected, or why the posted results are incomplete. Enrollment is listed as 18; the number contributing to each endpoint is not reported. The defensible reading is limited to the study’s stated objective, design, listed outcomes, and posted safety counts, without inferring an unreported concentration result or clinical effect.

13. Why This Trial Matters Statistically

This trial illustrates the distinction between asking whether a drug is present in a target tissue and asking whether treatment changes a clinical outcome. Its primary endpoint is lung tumor tissue concentration of metformin, expressed in ng/g, in a presurgical setting. That endpoint can address a pharmacologic question, while remaining distinct from a direct comparison of patient outcomes.

It also highlights how design labels affect interpretation. The record identifies a single-group study and says controls were not included in the primary analysis. It explicitly cautions that the arms are not a like-for-like control comparison. A control listing elsewhere in a record should not automatically be treated as a valid comparator for every endpoint. The question, outcome, and analysis population must align before a contrast can be interpreted.

The record also shows why outcome definitions and results need to be read together. The primary outcome is specified as a median with full range, while its description mentions a standard-deviation precision target. Without reported values or analysis details, readers cannot judge whether that target was achieved or how the concentration distribution behaved. A clear result requires both a defined measure and its numerical estimate, with information on uncertainty and the number of contributing observations.

Finally, the record is marked terminated and lists zero analyses, but does not report a reason for termination or numerical outcome results. Those gaps limit what can be concluded and illustrate the value of complete outcome reporting. The posted safety counts are also descriptive rather than a balanced comparative analysis. Statistical interpretation depends not only on a study’s objective but on the actual data, denominators, methods, and context documented in the record.

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 most consequential limitation for interpretation is that numerical primary and secondary concentration results are not reported in the registry record. The record therefore does not permit assessment of the observed tumor concentration, its range, or whether the stated precision goal was met. No confidence intervals or statistical analyses are listed.

The study is described as single group, with allocation NA and no masking. Although a control group appears in the safety record, the registry says controls were not included in the primary analysis and cautions that the arms are not a like-for-like comparison. The primary endpoint therefore has no reported randomized comparator. The record does not describe an analysis plan that would support causal comparisons.

Enrollment is listed as 18, but endpoint-specific denominators and analysis populations are not reported. The registry does not state how missing tissue or blood measurements were handled, how many participants contributed to each outcome, or why the safety at-risk counts differ from total enrollment. The reason the study was terminated is also not reported in the registry record.

The primary endpoint summary is specified as a median with full range, while the endpoint description refers to a standard deviation no greater than 25% of the mean. The record does not explain the relationship between these specifications or the method used to evaluate the precision target. A statistical analysis plan, multiplicity approach, and trial-specific sample-size justification are not reported. Together, these omissions leave both the results and their precision difficult to evaluate.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Metformin Pharmacology in Human Cancers: A Proof of Principle Study — NCT03477162.
• Registry record last updated 2023-10-03; status last verified 2022-11.
• Results first posted 2023-10-03.
• 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

NCT03477162 is an early-phase 1, single-group, presurgical study of metformin pharmacology in patients with surgically resectable thoracic tumors. Enrollment is listed as 18; the study is terminated. The record describes oral metformin before surgery and a primary endpoint of lung tumor tissue concentration, summarized as a median with full range within 7 days from surgery. Secondary outcomes include metformin concentrations in adipose tissue, tumor-adjacent normal tissue, plasma, and whole blood.

The registry record does not report numerical concentration results, statistical analyses, a reason for termination, or endpoint-specific denominators. Controls are excluded from the primary analysis, and the record cautions that the arms are not a like-for-like comparison. Safety counts list 0 serious adverse events in each group, 1 other adverse event in the Metformin group and 0 in the Control group, and 0 deaths in each group.