Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors (NCT02399215), a na phase 2 study. The primary outcome is PFS.

2. Clinical Question

The study asks how PFS and other outcomes were assessed among patients receiving nintedanib in this phase 2 setting. It is not a randomized comparison of nintedanib against another treatment or against no treatment. Consequently, any observed outcome would describe the enrolled group under the study conditions; by itself, it would not establish how outcomes would have differed under an alternative treatment.

The registry also lists clinical response by standard RECISTv1.1 criteria, overall survival, quality-of-life change, nintedanib plasma concentrations at steady state, and biomarker measures among secondary outcomes. These outcomes address different questions: tumor response, survival, patient-reported quality of life, drug exposure, and biological measurements. Their inclusion does not make them substitutes for the primary PFS endpoint.

3. Trial Design

This was a multicenter phase 2 study sponsored by Roswell Park Cancer Institute. The registry describes one treatment group and an enrollment of 32. The study is marked completed. Its start date is 2015-05-15, and its primary completion date is 2019-09-01. Those registry dates describe the study record; they do not establish when results were analyzed or published.

Participants received nintedanib by mouth twice daily on days 1–28, with courses repeating every 28 days in the absence of disease progression or unacceptable toxicity. The record lists additional study activities: laboratory biomarker analysis, pharmacological study, and quality-of-life assessment. It does not describe a control arm, random allocation, or masking; allocation is listed as not applicable and masking as none.

The primary endpoint was PFS, with time measured from therapy initiation to cessation for documentation of progressive disease or death. Assessment was planned up to 2 years. The stated analysis plan calls for Kaplan–Meier methods, a 90% confidence interval for median PFS using Greenwood’s formula, a confidence interval for the 16-week PFS rate using Jeffreys’ prior method, and Cox proportional hazards modeling of associations between survival and quantified variables.

Secondary outcomes listed include change in quality-of-life score, steady-state plasma concentrations of nintedanib at baseline and Week 8, clinical response measured using standard RECISTv1.1 criteria, median overall survival, and biomarker measures involving FGFR IIIb/IIIc, Ki-67, and microvessel density scores. The record lists 11 outcome measures overall, but does not give detailed results for them. A complete statistical analysis plan, eligibility criteria, treatment adherence details, and the rationale for the enrollment target 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

Reasons for not completing this period:

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 PFS, measured over Time interval from initiation of therapy, to its cessation for documentation of PD or death, assessed up to 2 years.

PFS is a time-to-event endpoint: it measures the time from a defined starting point until the first event specified by the endpoint. In this study, the starting point was initiation of therapy, and the listed events were cessation of therapy for documented progressive disease or death. Assessment was planned up to 2 years.

In general, time-to-event endpoints can retain information about when events occur, rather than reducing each participant’s outcome to whether an event occurred by a single assessment date. Kaplan–Meier methods estimate the event-free experience over time and can accommodate participants whose event time is not observed during follow-up, provided the analysis handles follow-up and censoring appropriately. The registry record does not explain the operational censoring rules or how incomplete follow-up was handled.

The planned summaries include median PFS with a 90% confidence interval and a 16-week PFS rate with a confidence interval. A median describes the time at which the estimated event-free proportion reaches its midpoint; a confidence interval conveys uncertainty around an estimate. The record specifies Greenwood’s formula for the median interval and Jeffreys’ prior method for the 16-week rate interval.

PFS is used in clinical research because it combines progression and death into a time-based outcome. Its interpretation depends on how progression is assessed, how event dates are assigned, and how participants without a recorded event are treated in the analysis. The registry record describes the intended endpoint and methods, but does not report the median, confidence interval, or 16-week PFS estimate. Thus the posted record does not permit a numerical assessment of the observed PFS.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record specifies a time-to-event primary endpoint and several planned statistical procedures. These methods describe how outcomes were intended to be summarized; they do not reveal the outcome estimates when results are not reported. No median PFS, interval estimate, or model result appears in the registry record.

What does Kaplan–Meier estimation do?

In general, the Kaplan–Meier method estimates the probability of remaining free of the event over time. It incorporates the timing of recorded events and can include participants whose follow-up ends before an event is observed. Such participants contribute information while they are followed; after follow-up ends, their later event status is unknown. This approach relies on appropriate handling of censoring and on assumptions about the relationship between censoring and event risk. The registry record names the method but does not report the censoring rules, number of events, follow-up distribution, or checks of those assumptions.

The primary endpoint combines documented progressive disease or death, using therapy initiation as the time origin. In general, a composite time-to-event endpoint reaches an event when any component specified by its definition occurs. Clear event definitions and consistent assessment are important because different event dates or progression criteria can affect estimated event times. The registry describes progression as documented and lists cessation for documentation of progressive disease or death, but further operational details are not reported in the registry record.

What does a median and its confidence interval communicate?

The median PFS is a point on the estimated event-time distribution. In general, it marks the time by which the estimated proportion remaining event-free has reached the midpoint. A confidence interval communicates uncertainty in the estimated median; a wider interval indicates less precision than a narrower interval. It does not mean that individual participant outcomes fall within that interval, and it does not give a probability that the fixed underlying median lies within a particular calculated interval.

The planned median interval is described as a 90% confidence interval calculated using Greenwood’s formula. In general, Greenwood’s formula estimates uncertainty in the Kaplan–Meier curve, which can then contribute to uncertainty estimates for features of that curve. The registry record does not report the interval’s endpoints or the information needed to review its calculation.

Why report a fixed-time PFS rate?

A PFS rate at a specified time summarizes the estimated proportion of participants who remain free of the defined event through that point. The record names the 16-week PFS rate and says its confidence interval would use Jeffreys’ prior method. In general, an interval around a rate communicates uncertainty in that estimate. A fixed-time rate and a median answer related but distinct questions: one concerns status at a chosen time, while the other describes a point in the event-time distribution. Neither estimate is reported in the registry record.

What would the Cox model add?

The planned Cox proportional hazards model was intended to investigate associations between survival and quantified variables. In general, a Cox model relates covariates to the event hazard over time without requiring a particular baseline hazard shape. The proportional hazards assumption concerns whether relative hazards associated with covariates remain stable over time. Model estimates are associations conditional on the variables included; they do not, by themselves, establish causation. The record does not name the quantified variables, give model specifications, report hazard ratios, or describe checks of model assumptions.

In a single-group study, a Cox model can explore whether measured characteristics are associated with event timing within the observed group. It does not create a randomized comparison or remove bias from unmeasured factors. Since no model results are reported, there is no association estimate to interpret.

How should planning illustrations be understood?

Any sample-size illustrations based on an observed effect are planning exercises, not observed power and not evidence that the study had adequate power for its outcomes. The stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of an observed effect. Those assumptions describe the illustration rather than this single-group study’s design. The registry record does not report the study’s own sample-size justification, and a two-arm illustration should not be mistaken for the design actually used.

For time-to-event illustrations, the stated approach concerns a total number of events; other illustrations concern participants per arm. In general, planning estimates depend on assumptions about the target effect, event occurrence, follow-up, and analysis. If those assumptions differ from the eventual study conditions, the illustration may not describe the study’s achieved precision. The record does not provide a prospective justification that would allow an assessment of the enrollment target.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including the primary PFS endpoint and secondary measures of response, overall survival, quality of life, drug concentrations, and biomarkers. When a study assesses multiple outcomes or multiple hypotheses, the chance of at least one apparently notable finding can increase if each is tested without an adjustment or a prespecified hierarchy. In general, multiplicity strategies may define a primary outcome, control an overall error rate, or treat secondary analyses as exploratory. The registry record does not report a multiplicity adjustment, testing hierarchy, or detailed statistical analysis plan.

The record lists 0 analyses. This is a registry reporting detail, not proof that no analysis was conducted. It also does not show whether outcome data were collected, whether analyses were completed elsewhere, or whether findings were omitted from the record. The numerical results for the primary endpoint and listed secondary outcomes are not reported in the registry record.

Missing data can affect interpretation when outcome measurements or follow-up are incomplete. For PFS, the handling of participants who stop follow-up or have no documented event is especially relevant because Kaplan–Meier estimation depends on how censoring is assigned and interpreted. For quality-of-life and biomarker outcomes, missing measurements can affect both the analyzed sample and the meaning of changes over time. The registry record does not report missing-data amounts, reasons, imputation methods, or sensitivity analyses.

The analysis populations are also not described in sufficient detail to determine who contributed to each outcome analysis. The record does not report whether all enrolled participants were included in the primary analysis, how eligibility or treatment exposure affected inclusion, or how participants who discontinued treatment were handled. These omissions limit assessment of completeness, potential selection, and the robustness of any result that might be reported elsewhere.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dyspnoea (9.4%), atrial fibrillation (6.2%), large intestinal obstruction (6.2%), anaemia (3.1%), acute myocardial infarction (3.1%).

The registry lists 32 participants at risk for serious adverse events and 32 at risk for other adverse events in the nintedanib group. It records 14 participants affected by serious adverse events and 31 affected by other adverse events. These are participant counts in the registry’s safety categories, not estimates of comparative risk against a control group.

The serious adverse event terms listed include dyspnoea at 9.4%, atrial fibrillation at 6.2%, large intestinal obstruction at 6.2%, anaemia at 3.1%, acute myocardial infarction at 3.1%, and myocardial infarction at 3.1%. The record also lists 18 deaths. It does not provide enough context in these figures to determine the timing, duration, severity grading, overlap between event categories, or relationship of individual events to treatment. The listed percentages should be understood as registry-reported values, not reinterpreted as causal effects.

In general, adverse event reporting describes events observed during a study; it does not by itself establish that the study treatment caused them. Causal interpretation ordinarily depends on clinical assessment, timing, competing causes, follow-up, and comparison with an appropriate control group. This single-group study has no such control group. The registry record also does not report a full safety analysis plan or detailed participant-level context. The counts therefore describe the safety information recorded, while leaving important questions about attribution and comparative frequency unresolved.

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

The record identifies a phase 2, single-group study of nintedanib in patients with locally advanced or metastatic neuroendocrine tumors. It describes a treatment schedule, a primary PFS endpoint, planned statistical methods, secondary outcomes, and selected adverse event counts. It also records enrollment of 32 and a completed status. These details establish what the study was designed to examine and some of the safety information entered in the registry.

The record does not report the primary PFS estimate, its planned 90% confidence interval, or the 16-week PFS rate. It does not report a treatment-effect estimate, a sponsor-reported hazard ratio, or numerical results for the listed secondary outcomes. As a result, the posted record cannot establish the observed duration of PFS, the precision of that estimate, or the direction and size of an association between survival and quantified variables.

Even if outcome estimates were available, the single-group design would not provide a randomized comparison. Outcomes among enrolled participants would not, by themselves, show what would have happened to comparable participants under an alternative treatment. Differences in who entered the study, the course of disease, follow-up, and other factors could influence observed outcomes. The available registry information does not support a causal claim about treatment benefit or harm.

The safety counts are useful as descriptions of events recorded among participants, but they also have limits. There is no control group for comparison, and the record does not give sufficient detail to infer treatment attribution from the counts alone. The listed deaths should likewise not be interpreted as treatment-caused deaths without further information.

In general, conclusions from a clinical study require both an estimate and an understanding of its uncertainty, completeness, and design. Here, the registry record supplies planned methods but not the primary numerical result or important analysis details. The appropriate interpretation is therefore bounded: the study’s question and methods can be described, and selected safety observations can be reported, but efficacy and comparative safety conclusions cannot be drawn from the registry record alone.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of how design determines what an analysis can answer. It is a single-group phase 2 study, not a randomized comparison. That distinction is central: statistical methods can describe event times and associations within the enrolled group, but cannot manufacture the counterfactual comparison that randomization would provide.

The primary endpoint also illustrates why the event definition and analysis plan matter. PFS depends on a defined origin, specified events, and follow-up. Kaplan–Meier estimation, a confidence interval for median PFS, a fixed-time PFS rate, and Cox modeling each address a different statistical feature. Naming these methods is not the same as reporting their estimates or showing that assumptions were met. The registry describes the intended methods but does not report the main endpoint findings.

The registry’s planned 90% confidence interval and 16-week rate interval make precision a relevant part of the proposed analysis. In general, estimates should be read together with uncertainty intervals: an estimate alone can conceal substantial imprecision. Here, neither the estimates nor their intervals are reported, so precision cannot be evaluated.

The record also lists numerous outcome measures. This raises general questions about prespecification and multiplicity: readers need to know which outcomes were primary, how secondary analyses were prioritized, and whether testing procedures were adjusted or considered exploratory. Those details are not reported in the registry record. Similarly, the absence of information about missing data and analysis populations prevents a full assessment of how complete and representative the analyzed observations would be.

Finally, the sample-size illustrations described for the accompanying statistical material are not the study’s own design justification. They are planning illustrations, not observed power, and their two-arm assumptions do not match the single-group design recorded for this study. Keeping these distinctions clear prevents a calculated planning scenario from being mistaken for a feature or result of the trial itself.

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 of the registry record is that it does not report the primary endpoint result. Without a median PFS, confidence interval, or 16-week PFS rate, readers cannot assess the observed event-time distribution or the precision of the planned estimates. Numerical results for the listed secondary outcomes are also not reported in the registry record.

The study’s single-group design limits interpretation independently of the missing results. It contains no randomized control group, so it cannot directly estimate a treatment contrast. Observed outcomes in participants receiving nintedanib would be descriptive of that group and could reflect factors other than treatment. The absence of masking, recorded as none, is relevant context for interpreting outcomes that involve assessment or reporting, although the registry does not detail how assessments were conducted.

Important analysis details are not reported in the registry record. These include the analysis populations, event adjudication procedures, censoring rules, follow-up completeness, missing-data methods, and checks of the assumptions behind the planned survival analyses. The registry names a Cox proportional hazards model but does not identify the modeled variables or report model results. It also does not provide a complete statistical analysis plan or a multiplicity strategy for the 11 outcome measures.

The safety information is limited to selected counts and event terms. The record does not establish the treatment attribution of reported events, provide a control-group comparison, or supply detailed context on timing and overlap. The enrollment target’s justification is not reported in the registry record, so its relationship to expected event counts or desired precision cannot be assessed. These limitations mean that the registry record is useful for identifying the study’s design and planned analyses, but insufficient for a complete evaluation of outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors — NCT02399215.
• Registry record last updated 2023-12-26; status last verified 2023-12.
• Results first posted 2022-06-28.
• 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

NCT02399215 is a completed, multicenter phase 2, single-group study sponsored by Roswell Park Cancer Institute. It enrolled 32 participants with locally advanced or metastatic neuroendocrine tumors. Participants received nintedanib by mouth twice daily on days 1–28, with courses repeating every 28 days unless progression or unacceptable toxicity occurred. The primary endpoint was PFS from therapy initiation to cessation for documented progressive disease or death, assessed up to 2 years.

The planned analysis used Kaplan–Meier methods, with a 90% confidence interval for median PFS, a confidence interval for the 16-week PFS rate, and Cox modeling of associations. The record lists 11 outcome measures, but does not report the primary numerical result or numerical findings for the listed secondary outcomes. It records 14 participants affected by serious adverse events, 31 affected by other adverse events, and 18 deaths, without a control group for comparison. The registry record does not report the study’s sample-size justification, detailed missing-data methods, or analysis populations.