This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Metformin and Carbohydrate Restriction With Platinum Based Chemotherapy In Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC) (NCT02019979), a na phase 2 study. The primary outcome is Progress Free Survival.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02019979 |
| Phase | Phase 2 |
| Condition | Non-small Cell Lung Cancer Stage IIIB/IV, Non-small Cell Lung Cancer Metastatic, Nonsquamous Nonsmall Cell Neoplasm of Lung |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 14 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Beth Israel Medical Center |
| Results posted | Yes |
2. Clinical Question
The clinical question concerns a combined treatment approach for people with stage IIIB/IV non-squamous non-small cell lung cancer. The intervention was metformin and a carbohydrate-restricted diet added to a platinum-based chemotherapy regimen. The primary outcome was progression-free survival, defined as time from the first treatment dose until disease progression under RECIST 1.1 or death from any cause, whichever occurred first.
Population
People with stage IIIB/IV non-squamous non-small cell lung cancer, including metastatic disease as reflected in the registry’s condition list.
Intervention
Metformin and a carbohydrate-restricted diet added to platinum-based chemotherapy.
Comparator
No separate comparison arm is described. The registry identifies a single-group study, so the treatment approach is not compared with a concurrent control group in this record.
Primary question
What progression-free survival was observed after treatment began? The registry record does not report the primary endpoint result.
The registry describes a phase 2 study with enrollment of 14 participants. Its status is terminated. Those design details define the scope of the evidence: the record concerns an enrolled group receiving the combined regimen, rather than a randomized contrast that could estimate a treatment difference against a control group.
The registry’s rationale discusses metformin’s proposed relationship to AMPK, cellular energy processes, and mTOR signaling. That rationale explains the biological motivation recorded for studying metformin; it is not evidence that the treatment changed those pathways in participants or affected clinical outcomes. The record also lists overall survival and the number of participants with an LKBI mutation as secondary outcomes, but does not report their results.
3. Trial Design
The METRO Study is listed as a phase 2, single-group trial of metformin and a carbohydrate-restricted diet added to platinum-based chemotherapy for stage IIIB/IV non-squamous non-small cell lung cancer. Enrollment was 14. The registry records a start in 2013-12, primary completion in 2016-12, and a terminated status. It does not report why the study was terminated.
There is no concurrent control arm described in the registry record. Allocation is listed as not applicable, and masking is listed as none. These features mean the record does not describe random assignment or blinded treatment assessment. The listed intervention is a combination: metformin and a carbohydrate-restricted diet were added to a platinum-based chemotherapy regimen. The record does not provide further detail about chemotherapy choices, treatment schedules, adherence, or changes to treatment over time.
The registry identifies progression-free survival as the primary outcome, with a measurement window described as time after day 1 of cycle 1 to first disease progression for up to 20 months. Its outcome definition starts at the first treatment dose and ends at the earlier of disease progression per RECIST 1.1 or death from any cause. The record lists overall survival and number of participants with an LKBI mutation as secondary outcomes. It does not report results for these outcomes.
A single-group design can describe outcomes among the enrolled participants, but it does not provide a direct randomized comparison with another treatment strategy. Any interpretation of an observed outcome would therefore need to account for the lack of a concurrent control and the small enrollment. In this record, the primary endpoint estimate itself is not reported, so even a descriptive estimate of progression-free survival cannot be assessed from the registry information.
The registry record does not report the eligibility criteria in detail, the statistical analysis plan, the intended sample-size justification, or the reasons for termination. Those omissions leave important design and conduct questions unresolved. They should not be filled in by assuming what is customary for a phase 2 study.
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
| Stage | Metformin /Carbohydrate Restricted Diet |
|---|---|
| STARTED | 14 |
| COMPLETED | 0 |
| NOT COMPLETED | 14 |
Reasons for not completing this period:
| Reason | Metformin /Carbohydrate Restricted Diet |
|---|---|
| study terminated | 14 |
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.
| Characteristic | Unit | Metformin /Carbohydrate Restricted Diet |
|---|---|---|
| Participants analysed | 14 | |
| Age, Continuous | years | 66.71 (SD 6.24) |
| Sex: Female, Male: Female | Participants | 8 |
| Sex: Female, Male: Male | Participants | 6 |
6. Primary Endpoint
The registry lists the primary outcome as Progress Free Survival, measured over Time after day 1 cycle 1 to first disease progression for up to 20 months.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Full Range |
| Unit | months |
| Endpoint classification | Time-to-Event Analysis |
Progression-free survival is a time-to-event outcome. In this trial, the clock begins at the first treatment dose. The event is the earlier of disease progression assessed under RECIST 1.1 or death from any cause. The registry describes the outcome timeframe as time after day 1 of cycle 1 to first disease progression for up to 20 months.
Time-to-event outcomes are used when both whether an event occurs and how long it takes are relevant. They can retain information about timing that would be lost in an outcome recorded only as a yes-or-no status at a single assessment. In general, time-to-event analysis can also account for participants whose event time is not observed during follow-up, provided the analysis records their follow-up appropriately. The registry record does not report how censoring was handled in this study.
The listed summary parameter is the median, with full range as the dispersion measure. A median time-to-event estimate describes the point by which half of the analyzed group has experienced the event, under the relevant analysis definition. The full range describes the spread between the smallest and largest observed values, but does not by itself show the precision of the median. Confidence intervals and details of the endpoint analysis are not reported in the registry record.
Because progression-free survival includes death from any cause as an event, it is not limited to radiographic progression. The endpoint definition is explicit about that composite event, but the registry does not provide the observed estimate or the number of events. The outcome therefore cannot be quantitatively interpreted from this record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a clinically relevant time-to-event endpoint, but it does not report the primary progression-free survival result. There is no median estimate, full range, confidence interval, or event count in the record. Consequently, the duration of progression-free survival in the enrolled group and the precision of any estimate cannot be judged from the registry record.
The design also limits what a result could establish. This was a single-group study with no concurrent comparison arm. An outcome observed in participants receiving metformin, a carbohydrate-restricted diet, and platinum-based chemotherapy would describe that treatment group; by itself, it would not separate the contribution of each component or establish how the outcome compares with another treatment approach. Differences between this group and participants treated elsewhere or at another time would not constitute a randomized comparison.
Enrollment was 14, and the study is listed as terminated. A small enrolled group generally yields limited information about outcome variability and uncommon events. That general limitation does not determine what happened in this trial, and the reason for termination is not reported in the registry record. The record does not supply enough detail to assess whether all enrolled participants contributed to the primary analysis or how long they were followed.
The secondary outcomes listed are overall survival and the number of participants with an LKBI mutation. Their results are not reported in the registry record. Nor does the record provide an analysis count, a statistical analysis plan, or sponsor-reported hazard-ratio estimates. Without outcome estimates and their uncertainty, there is no basis for judging the magnitude or precision of an association in this trial.
The registry’s mechanistic rationale refers to AMPK and mTOR. Such biological motivation can support why a combination was studied, but a proposed pathway is distinct from a measured clinical result. The registry record does not report whether pathway activity was measured, whether it changed, or whether any such change was related to progression-free survival.
Overall, the available registry information describes the question and broad design, not a quantitative answer. The status and enrollment should be read as trial-record details, not as evidence for or against the treatment strategy. No conclusion about efficacy can be drawn from the missing primary outcome result, and the single-group design would in any case not provide a randomized treatment contrast.
9. Statistical Methods Explained
The main statistical issue is that the primary outcome is time to an event rather than a measurement taken at a fixed moment. The event definition combines progression per RECIST 1.1 and death from any cause, using whichever occurs first. This makes progression-free survival a composite endpoint: either component can end the measured interval. In general, composite outcomes are interpreted according to their stated components, because a summary does not necessarily reveal which component accounts for the events.
What does the median represent?
The registry lists the median as the summary parameter. In general, the median of a time-to-event distribution is the time by which half of the population represented by the analysis is estimated to have experienced the event. It is a measure of the event-time distribution, not a comparison between treatment groups. In a single-group study, a median can describe the enrolled group if the analysis and follow-up support its estimation. The registry does not report the median progression-free survival estimate, so no value can be interpreted.
The record also names the full range as the dispersion measure. A range communicates the observed lower and upper endpoints of the reported values. It does not provide the same information as a confidence interval: a range describes the span of observed data, while a confidence interval expresses uncertainty around an estimated quantity under a statistical procedure. The registry record does not report a confidence interval or explain how uncertainty was quantified.
Why does censoring matter?
In general, some participants may not have an observed event before their available follow-up ends. Their event time is then not known exactly; time-to-event methods can use the time they were observed without treating the end of observation as if it were the event. This is called censoring. The validity of many such methods depends on how observation ends in relation to the event process. The registry record does not describe censoring rules, loss to follow-up, follow-up completeness, or the number of participants with an event. These omissions make it impossible to evaluate how the stated time-to-event endpoint was analyzed.
For a time-to-event comparison, a hazard ratio is often used to express a relative event rate over follow-up under a specified model. A hazard ratio is not a ratio of median times and does not directly state an absolute difference in survival time. Its interpretation depends on the analysis assumptions and the comparison groups. Here, the study is identified as single-group, and no sponsor-reported hazard-ratio estimate is included in the registry information. A comparative hazard ratio cannot be inferred from the design description alone.
What can a single-group design estimate?
In general, a single-group study can estimate outcomes among participants who received the studied regimen, subject to the quality of follow-up and analysis. It cannot directly estimate a randomized contrast with a control arm when none is present. The treatment in this record combines metformin and a carbohydrate-restricted diet with platinum-based chemotherapy. An observed outcome would therefore reflect the participants and the combined treatment context; the design cannot isolate the effect of metformin from the diet or chemotherapy.
Allocation is listed as not applicable, the model as single group, and masking as none. Those entries describe the registered design. They do not establish that outcome assessment was biased, but they mean the registry does not describe random allocation or masking as protections against some forms of bias. The record does not state whether progression assessments were conducted by blinded reviewers or whether any other safeguards were used.
How should planning illustrations be read?
General sample-size planning estimates how many participants or events would be needed to detect a specified effect under chosen assumptions. Such a calculation is not an observed result and does not show the probability that the trial found a true effect. The planning illustration associated with the record is described as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event outcomes, it is described as giving the total number of events. These are planning assumptions, not a description of the actual single-group trial design.
The record does not report the trial’s own sample-size justification or design assumptions. A planning calculation framed around two arms should not be mistaken for evidence that this trial had two arms: the registered study model is single group. Nor should a planning illustration based on an observed effect be called observed power. It is a hypothetical design calculation under stated assumptions, not a measure of what the completed study proved.
Over-dispersion is a general concern when observed variation is greater than a statistical model assumes. If a model underestimates variation, uncertainty intervals may be too narrow and tests may be overly optimistic. The registry information does not identify an over-dispersion analysis for this trial, and the outcome estimates needed to assess variability are not reported. This general concept therefore cannot be used to characterize the trial’s actual analysis.
Finally, a complete interpretation would require the analysis population, endpoint data, censoring details, and uncertainty estimates. The registry reports enrollment of 14 and lists outcome names, but it does not report whether all enrolled participants were included in each analysis, how missing outcome information was handled, or whether analyses were adjusted. Those methods should be treated as unknown rather than reconstructed from the endpoint label.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists progression-free survival as the primary outcome and names overall survival and the number of participants with an LKBI mutation as secondary outcomes. Considering multiple outcomes raises a general multiplicity issue: when several hypotheses are tested, the chance of at least one apparently notable result can increase if each is assessed without adjustment. Whether and how to address multiplicity depends on the prespecified analysis plan and the role assigned to each outcome. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or inferential results for these endpoints.
The record reports zero analyses. This means no analysis results are listed in the registry information; it should not be read as evidence that investigators conducted no analyses outside the record. The registry does not provide a statistical analysis plan, prespecified analysis populations, or an account of deviations from planned methods. Those details are not reported in the registry record.
Missing data and incomplete follow-up are particularly relevant to progression-free survival because participants may have different observation times. The record does not describe censoring, loss to follow-up, missing assessments, or the number of participants contributing data to the primary endpoint. It also does not state how missing values for the secondary outcomes were handled. Without these details, the completeness and representativeness of the analyzed data cannot be evaluated.
The registry’s enrollment figure is not a substitute for an analysis-population count. It does not establish that every enrolled participant received treatment, had an endpoint assessment, or was included in each outcome analysis. No such counts are reported. The appropriate interpretation is therefore limited to the registered design and outcomes, with the analysis methods and results remaining unavailable in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Metformin /Carbohydrate Restricted Diet | 1 | 14 | 7.1% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Metformin /Carbohydrate Restricted Diet | 0 of 14 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Metformin /Carbohydrate Restricted Diet | 1 of 14 |
Most frequent serious adverse event terms
| Event term | Organ system | Metformin /Carbohydrate Restricted Diet |
|---|---|---|
| Nausea | General disorders | 1 of 14 |
| Reflux | Gastrointestinal disorders | 1 of 14 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Metformin /Carbohydrate Restricted Diet |
|---|---|---|
| Fatigue | General disorders | 1 of 14 |
| Anemia | Blood and lymphatic system disorders | 1 of 14 |
| Nausea | General disorders | 1 of 14 |
| Leukopenia | Blood and lymphatic system disorders | 1 of 14 |
| Hypoalbuminemia | Metabolism and nutrition disorders | 1 of 14 |
Serious events with the highest arm-level rate: nausea (7.1%), reflux (7.1%).
The registry lists one serious adverse event group, titled metformin / carbohydrate restricted diet, with 14 participants at risk and 1 affected. It also records 0 deaths in that group. These are descriptive counts for the recorded group; they do not by themselves establish whether an event was caused by the study regimen or whether the regimen changed risk relative to another treatment.
Nausea and reflux are listed among the top serious terms, each with a reported frequency of 7.1%. The record does not clarify whether these terms refer to the same affected participant, whether they represent separate events, or how event coding and attribution were handled. The percentages should therefore be read as registry-reported figures, not converted into a participant count or used to infer a pattern beyond what is recorded.
Safety data from a group of this size provide limited information about uncommon events. In general, absence of a recorded event does not establish that an event cannot occur, and a count does not establish causation. The record does not provide a control group, detailed event narratives, severity grades beyond the serious-event classification, or a full account of follow-up for safety. The listed figures describe what the registry records; they do not support comparative safety conclusions.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a phase 2, single-group study evaluated metformin and a carbohydrate-restricted diet added to platinum-based chemotherapy for stage IIIB/IV non-squamous non-small cell lung cancer. It records enrollment of 14 and identifies progression-free survival as the primary outcome. It also lists overall survival and the number of participants with an LKBI mutation as secondary outcomes.
The record does not report the primary endpoint estimate or the secondary outcome results. It therefore does not show how long participants remained progression-free, how precise an estimate might be, or what was observed for overall survival or LKBI mutation. The terminated status is recorded, but the reason for termination is not reported in the registry record. These missing results should not be replaced with assumptions based on the study rationale or design.
Even if an outcome estimate were available, a single-group study would describe outcomes in the enrolled group rather than provide a randomized comparison against a control group. The combined regimen also prevents attribution of an observed outcome to metformin or the diet alone. These design features do not make the descriptive data meaningless; they define the limits of what those data could answer.
The mechanistic rationale involving AMPK and mTOR explains why the combination was of interest, but it does not establish a clinical effect. Similarly, the safety counts are descriptive and do not demonstrate causation or comparative risk. The record contains no basis for a treatment recommendation, and no treatment decision should be inferred from an unreported endpoint result.
The most defensible conclusion is narrow: the registry describes the study question, intervention, broad design, enrollment, and selected safety information, while leaving the clinical outcome results and key analysis details unavailable. The posted record cannot quantify efficacy or support a comparison with another approach.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of the difference between a registered research question and a reported result. The record gives a defined time-to-event endpoint and a biological rationale, but it does not provide the primary estimate or its uncertainty. Naming an endpoint is not equivalent to reporting evidence about that endpoint.
The design also makes the distinction between description and comparison important. With a single group, an outcome can describe what happened among enrolled participants, but a treatment effect relative to a control requires a valid comparison. The combined regimen adds a further interpretive constraint: outcomes cannot be assigned separately to metformin, the carbohydrate-restricted diet, or platinum-based chemotherapy from this design alone.
The enrollment of 14 highlights why precision and completeness matter when interpreting small studies. In general, estimates from limited groups can be sensitive to the outcomes of individual participants, while uncommon events may not be well characterized. Here, the registry does not report the endpoint estimate, confidence interval, event count, or analysis population, so the actual precision cannot be assessed.
The record also illustrates why planning calculations must be kept distinct from trial results. A planning illustration based on an observed effect and two-arm assumptions is not evidence that the registered single-group study conducted a randomized comparison, and it is not observed power. Statistical calculations answer questions only under their stated design assumptions.
Finally, transparent reporting of termination reasons, missing-data handling, analysis populations, and outcome estimates would help readers judge how much confidence to place in findings. Those details are not reported in the registry record. The principal statistical lesson is not a claim about treatment benefit, but the need to distinguish biological plausibility, study design, outcome measurement, and reported evidence.
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 direct limitation is that the registry record does not report the progression-free survival result, despite identifying it as the primary outcome. It also does not report confidence intervals, event counts, or the number of participants included in the endpoint analysis. The magnitude and precision of the primary outcome therefore cannot be assessed.
The single-group design has no concurrent control arm, so it cannot provide a randomized estimate of the difference between the combined regimen and another strategy. The regimen itself includes metformin, a carbohydrate-restricted diet, and platinum-based chemotherapy, making separate attribution to its components unavailable. Masking is listed as none, while the record does not explain how outcome assessments were performed.
Enrollment was 14, and the study is listed as terminated. The reason for termination is not reported in the registry record. The record also does not provide detailed eligibility criteria, treatment exposure, adherence, follow-up completeness, censoring rules, or missing-data procedures. These omissions prevent assessment of who contributed to each outcome and how incomplete observation may have affected estimates.
The named secondary outcomes have no reported results. The analysis plan, multiplicity approach, prespecified populations, and sample-size justification are also not reported in the registry record. The serious adverse event figures are descriptive, with no concurrent comparator or detailed account of event attribution. Taken together, these limitations mean the record supports a description of the registered study and limited safety counts, but not a quantitative assessment of clinical outcomes or comparative effects.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Metformin and Carbohydrate Restriction With Platinum Based Chemotherapy In Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC) — NCT02019979.
- Registry record last updated 2018-05-04; status last verified 2018-03.
- Results first posted 2018-05-04.
- 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.
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18. Record Summary
The METRO Study is registered as a phase 2, single-group study of metformin and a carbohydrate-restricted diet added to platinum-based chemotherapy for stage IIIB/IV non-squamous non-small cell lung cancer. Enrollment was 14. The record lists a start date of 2013-12, primary completion in 2016-12, and terminated status. Allocation is listed as not applicable and masking as none.
Progression-free survival is the primary outcome, defined from the first treatment dose to progression per RECIST 1.1 or death from any cause, whichever comes first. The record also lists overall survival and number of participants with an LKBI mutation as secondary outcomes. The primary and secondary outcome results are not reported in the registry record.
The serious adverse event group records 14 participants at risk, 1 affected, and 0 deaths. Nausea and reflux are each listed at 7.1% among the top serious terms. These figures are descriptive and do not establish causation or comparative risk. The registry does not report the reason for termination, the analysis plan, or detailed missing-data and follow-up methods.