Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas (NCT00030264), a na phase 2 study. The primary outcome is Time to Disease Progression.

2. Clinical Question

This design addresses how progression was observed among participants receiving the combination, rather than whether the combination changed progression compared with an alternative. The record lists 23 participants as enrolled and states that 20 subjects were analyzed for time to progression. It separately notes that 3 subjects were not included in the response analysis because of loss to follow-up or progression of a comorbid condition requiring early termination. The record does not clarify whether that response-analysis note describes the same analysis population as the primary time-to-progression outcome.

3. Trial Design

This was a phase II, single-group study sponsored by Children's Hospital of Philadelphia. The registry lists 23 participants as enrolled. It describes the intervention as methotrexate and vinblastine, administered once a week for the first 26 weeks and then every two weeks for the next 26 weeks, or until disease progression, whichever occurred first. The study is marked completed.

The design was not randomized: allocation is listed as not applicable. Masking is listed as none. All participants were assigned to the one described treatment group, so there was no concurrent control group in the registry record. This allows the study to describe outcomes observed during treatment, but it does not provide a like-for-like comparison with another treatment or usual care.

The primary outcome was time to disease progression, recorded in months, with a mean as the summary measure and the full range as the dispersion. Its timeframe is listed as 6 months. Disease progression was assessed clinically and radiographically, using magnetic resonance imaging whenever possible, or computed tomography and/or physical examination of palpable lesions. The record states that a treating physician or designee assessed clinical progression.

The record reports that 20 subjects were analyzed for time to progression. It also says 3 subjects were not included in the response analysis: 2 were lost to follow-up, and 1 had progression of a comorbid condition requiring early termination. The record does not report a detailed participant flow, the analysis population definition, or a statistical analysis plan. No inferential analysis is listed in the registry record. The primary outcome's observed mean and full range 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: 20 subjects were analyzed for time to progression. 3 subjects were not included in the response analysis due to lost to follow up (N=2) or progression of comorbid condition which required early termination (N=1)

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 Time to Disease Progression, measured over 6 months.

The primary endpoint is time to disease progression, measured in months. It is intended to describe how long participants remain without a recorded progression event under the study's assessment approach. Time to progression is useful when the timing of a clinically defined event is important, rather than only whether the event occurred at a single assessment.

In this trial, progression could be identified radiographically or clinically. Radiographic assessments used magnetic resonance imaging whenever possible, or computed tomography and/or physical examination measurements of palpable lesions. Clinical progression was assessed by the treating physician or designee. The registry definition includes the appearance of new lesions, an increase in the size of index tumors by at least 25% of the sum of the products of baseline measurements, and/or an increase in symptoms.

The outcome is summarized in the registry as a mean with the full range, and its timeframe is listed as 6 months. These labels describe the intended summary and assessment period, but do not supply the observed mean or range. Neither the mean time to progression nor the range is reported in the registry record. Thus, the outcome definition can be described, but the posted information does not allow the observed timing or its variability to be quantified.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information available is limited. The registry describes a phase II study with one treatment group, no allocation to a comparator, and no masking. It lists time to disease progression as the primary outcome, summarized by a mean and full range. No analysis is listed in the registry record, and the observed mean and range are not reported. The explanations below describe general statistical concepts relevant to this outcome; they do not imply that a particular unreported method was used.

What does a time-to-progression outcome represent?

In general, a time-to-event outcome records the time from a defined starting point until an event occurs. Here, the event is disease progression, assessed by clinical and radiographic criteria. Time-to-event data can be useful because they retain information about when progression is observed, rather than reducing each participant's experience to a simple event/no-event label. The registry describes the outcome in months and lists a 6-month timeframe, but does not report the starting point or further details about follow-up for this analysis.

Some time-to-event analyses can account for participants whose event time is not observed during the available follow-up. This is often called censoring: the analysis uses the fact that a participant was known to be event-free up to a particular point, without treating that point as the event time. The registry record does not state whether censoring occurred, how it was defined, or how incomplete follow-up was handled. It would therefore be inappropriate to assume that a specific time-to-event estimator or model was used.

What do a mean and full range tell the reader?

In general, a mean is an average of observed values. It can give a compact description of the recorded times, but it may be affected by unusually short or long observations. A full range gives the smallest and largest observed values and conveys the span of the data; it does not show how observations are distributed between those endpoints. The registry identifies these as the intended summary measures, but does not report their values. Their absence prevents interpretation of either the average or the observed spread.

A confidence interval is a statistical summary of uncertainty around an estimate. It reflects both the observed data and assumptions of the method used to calculate it. It is not the same as the full range of participant observations. No confidence interval or other uncertainty estimate for the primary outcome is reported in the registry record. Without an estimate and its uncertainty, readers cannot judge the precision of the primary result.

Why does the single-group design matter?

In general, a randomized comparison can estimate a difference between groups while balancing, on average, factors that may affect outcomes. This study has one group and no randomized comparator, so it can describe the outcomes recorded in that group but cannot estimate a randomized treatment contrast. Changes over time could reflect the course of the condition, participant characteristics, assessment practices, or other influences as well as treatment. This is a design limitation, not a statistical adjustment that can be resolved from the posted aggregate information.

The registry lists no masking. In general, knowledge of treatment assignment can influence clinical judgments or assessment decisions, particularly when an endpoint includes clinical assessment. Radiographic criteria may provide structured measurements, but the record does not describe assessor blinding or procedures used to maintain consistency. It is not possible to determine from the registry entry whether these factors affected assessments.

What can be inferred from the sample-size illustration?

The planning illustration is described as a calculation based on the observed effect, not the study's own design. Its stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. The record also says that time-to-event planning uses a total event count, while other planning results use participants per arm. These assumptions describe a planning exercise, not the actual single-group design. Such sample sizes are planning illustrations and are not observed power. The registry does not report the trial's own sample-size justification, so the illustration should not be treated as evidence about the design rationale or the precision actually achieved.

What is over-dispersion, in general?

For count outcomes, over-dispersion means that observed variability exceeds what a simple statistical model assumes. If it is ignored, uncertainty estimates can be too small and tests can appear more conclusive than they are. This is a general statistical concept; the primary endpoint is time to progression, and the registry record does not report an over-dispersion analysis or a count model. It is not a method that can be assumed for this trial.

What can be said about analyses and adjustment?

The registry lists one outcome measure and no analyses. It does not report model specifications, covariate adjustment, hypothesis tests, interim analyses, or a plan for multiple testing. Because those details are absent, readers cannot assess whether analyses were adjusted, how decisions were made, or whether additional outcomes influenced interpretation. General statistical principles can explain why these choices matter, but they cannot fill gaps in the registry record. The primary result itself, including its observed mean and range, is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and no analyses. It identifies time to disease progression as the primary outcome, but does not report a statistical analysis plan, a prespecified hierarchy of outcomes, or whether additional hypotheses were tested. The handling of multiplicity is therefore not reported in the registry record. In general, testing multiple outcomes or multiple versions of an analysis can increase the chance of a nominally positive finding arising by chance. Whether that concern applies to any analyses conducted cannot be determined from this entry.

Missing-data information is limited. The record says 20 subjects were analyzed for time to progression. It separately notes that 3 subjects were not included in the response analysis: 2 were lost to follow-up, while 1 had progression of a comorbid condition that required early termination. The record does not clarify whether those 3 were also excluded from the primary time-to-progression analysis, how the analysis population was defined, or whether any follow-up times were incomplete.

In general, missing follow-up can affect a time-to-event estimate if the reason for loss is related to a participant's chance of progression. Methods can address incomplete observation under stated assumptions, but the registry record does not specify whether such methods were used or what assumptions they required. It also does not report sensitivity analyses to assess the effect of missing data. The analysis population, missing-data handling, and multiplicity approach are therefore not reported in the registry record, limiting reproducibility and assessment of possible bias.

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: infection - bacterial (4.3%), hepatic - other - cholecytitis (4.3%), anorexia (4.3%), pulmonary - other - respiratory distress (4.3%), infection - viral (4.3%).

The registry lists 23 participants at risk for serious adverse events and reports that 6 were affected. It also lists 23 at risk for other adverse events and reports that 8 were affected. Three deaths are recorded. These are counts in the treatment group, not comparisons with a control group; they do not establish whether an event was caused by the treatment.

The registry lists six serious adverse-event terms at 4.3% each: Infection - Bacterial, Hepatic - Other - Cholecytitis, Anorexia, Pulmonary - Other - Respiratory Distress, Infection - Viral, and Febrile neutropenia. These terms describe reported event categories. The record does not give further detail about event severity, timing, recurrence, or attribution, and the listed percentages should not be treated as comparative risks.

The 3 recorded deaths are a separate safety count. The registry record does not report whether they were considered related to treatment, the causes of death, or when they occurred. These aggregate safety figures should therefore be read as descriptive reports for this group, not as proof of treatment causation or as a basis for comparing safety with another option.

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

The record documents a phase II, single-group study of methotrexate and vinblastine in patients with neurofibromatosis type 1 and progressive plexiform neurofibromas. It describes the treatment schedule, defines progression using clinical and radiographic assessments, and identifies time to disease progression as the primary outcome. It also reports that 20 subjects were analyzed for that outcome and gives aggregate adverse-event counts for the treatment group.

However, the primary outcome's observed mean and full range are not reported in the registry record. Without those results, the posted information does not show the observed time to progression or its variability. It also does not include an uncertainty estimate for the primary outcome. The study's registry entry therefore does not support a quantitative conclusion about the progression experience recorded during the study.

The design does not include a randomized comparator. As a general principle, observations in a single group do not show how the same participants would have fared under a different treatment or without the study regimen. The record can describe what was reported among participants receiving the combination, but it cannot establish a comparative treatment effect. The absence of masking is another design feature to consider when clinical judgment contributes to outcome assessment.

The safety counts are also descriptive. The registry reports serious and other adverse events, as well as deaths, but does not report whether deaths or specific events were attributed to treatment. With no comparator, the counts cannot establish excess risk relative to another group. In addition, missing-data details and the relationship between the primary and response-analysis populations are not fully described.

In short, the registry record provides useful information about the study's design, regimen, outcome definition, and reported safety counts. It does not report the primary outcome estimate or a comparative analysis. Those omissions place clear limits on what can be concluded from the posted results.

13. Why This Trial Matters Statistically

This trial illustrates the distinction between defining an outcome and reporting its result. The registry gives a detailed progression definition that includes new lesions, a specified increase in index-tumor measurements, and increased symptoms. It also describes radiographic and clinical assessment methods. Yet the mean time to progression and full range named as the primary summary are not reported in the registry record. A well-defined endpoint cannot by itself show what was observed or how precisely it was estimated.

The single-group design is also statistically consequential. The study can describe outcomes recorded among participants receiving the combination, but it has no randomized control group for a direct contrast. This makes it important to distinguish a treatment-group description from evidence of a treatment difference. The record also lists no masking, which matters when clinical assessments contribute to determining progression.

The participant counts highlight a separate reporting issue. The record reports 20 subjects analyzed for time to progression, while describing 3 exclusions from response analysis and giving reasons for those exclusions. It does not clarify how those populations relate. Clear definitions of analysis populations and transparent accounting for incomplete follow-up are important because they help readers assess how the analyzed data relate to enrollment.

Finally, the safety counts show why descriptive event reports require careful interpretation. Counts and listed event terms can convey what was recorded, but without attribution details and a comparison group they do not establish causality or comparative risk. Together, these features make the record a useful example of how design, endpoint reporting, analysis-population definitions, and safety context shape statistical interpretation.

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 main limitation for interpreting efficacy is that the registry names a primary outcome but does not report its observed mean or full range. No confidence interval or other precision estimate for that outcome is reported in the registry record. As a result, the primary progression result cannot be quantitatively described from the posted information.

The study has a single treatment group, with allocation listed as not applicable and masking listed as none. There is no randomized comparator for estimating a treatment contrast. Clinical assessment contributed to the progression definition, and the record does not describe assessor blinding or procedures for standardizing those judgments.

The record states that 20 subjects were analyzed for time to progression and separately reports that 3 subjects were not included in response analysis because of loss to follow-up or a comorbid condition requiring early termination. It does not explain whether these populations overlap, how incomplete follow-up was treated, or whether sensitivity analyses were conducted. These omissions make it difficult to assess the effect of missing data on the primary outcome.

The registry does not report the statistical analysis plan, model details, interim analyses, multiplicity handling, or the trial's sample-size justification. The planning illustration is not the trial's own design and does not establish observed power. Safety data are aggregate counts without reported attribution for deaths or a comparator group. Taken together, these limitations restrict assessment of precision, reproducibility, and causal interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas — NCT00030264.
• Registry record last updated 2018-08-08; status last verified 2018-07.
• Results first posted 2018-08-08.
• 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

This completed phase II study evaluated methotrexate and vinblastine in patients with neurofibromatosis type 1 and progressive plexiform neurofibromas. The registry describes one treatment group, no random allocation, and no masking. The regimen was once a week for the first 26 weeks, then every two weeks for the next 26 weeks or until disease progression, whichever occurred first.

The primary outcome was time to disease progression, summarized as a mean and full range, with a timeframe of 6 months. The record says 20 subjects were analyzed for that outcome, but the observed mean and range are not reported in the registry record. It separately reports 3 subjects not included in response analysis due to loss to follow-up or progression of a comorbid condition.

For safety, the registry lists 23 participants at risk, 6 affected by serious adverse events, 8 affected by other adverse events, and 3 deaths. The record does not report attribution for the deaths. No randomized comparator is available for comparative interpretation.