R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas (NCT00021541), a randomized phase 2 study. The primary outcome is Median Time to Progression.

2. Clinical Question

The trial also sought to examine treatment-related side effects, and quality of life was listed as a secondary outcome. The registry summary describes the biological rationale as interference with ras and other proteins involved in cell growth. That rationale explains why the investigators studied tipifarnib, but it is not itself evidence about the clinical outcome. The trial was completed, with enrollment of 62. Its recorded primary-completion date was 2009-02-19.

3. Trial Design

The registry identifies this as a phase II randomized, cross-over trial with 62 enrolled participants. It lists the masking as single. The official title calls the study double-blinded, so the registry record contains different descriptions of masking; the record does not explain that difference. The study is marked completed, and its recorded start date is 2001-07-17.

Participants were assigned to treatment sequences. One sequence began with tipifarnib and then moved to placebo; the other began with placebo and then moved to tipifarnib. The arm descriptions specify oral treatment in repeating courses, with treatment on days 1 through 21. The tipifarnib arm description gives a dose of 200 mg/m^2/dose based on body surface area every 12 hours. The placebo description states that courses repeat as in the other arm. The registry record does not provide further detail about the timing or conduct of the transition between treatment periods.

A cross-over design lets each participant receive both assigned treatments in sequence. In general, this can make within-participant comparisons useful because characteristics that remain stable within a person do not differ between that person’s treatment periods. It also means that interpretation depends on the timing of outcomes, the sequence, and whether effects from an earlier period persist into a later period. Those are general features of cross-over studies, not reported findings about this trial. The registry record does not report whether a washout period was used or how period and carry-over effects were handled.

The primary-outcome population description says that 62 started phase A, with 2 ineligible, and that 43 started phase B. Those counts describe different phases and should not be treated as a single complete analysis population. The registry record does not explain why the listed phase B count differs from the phase A count or provide a full participant flow by sequence. It also does not report the randomization method, allocation concealment, or a sample-size justification. The study’s official title describes a placebo-controlled design, consistent with the listed interventions and sequences.

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.

Period 1-First Treatment

Reasons for not completing this period:

Period 2-crossover

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: phase A - 62 started and 2 were ineligible = 60 phase B - 43 started

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 Median Time to Progression, measured over 8 years.

The primary endpoint was median time to progression, in months, with an 8 years timeframe recorded. The endpoint measures how long it takes for a participant to meet the trial’s defined progression criterion, starting from the beginning of phase A or phase B. Progression was defined as an increase of at least 20% in the sum of the volumes of all index lesions, based on volumetric analysis using MRI.

Time-to-event outcomes are useful when the timing of an event matters and participants may have different lengths of follow-up. A median time identifies the point by which half of the relevant population has experienced the event, under the analysis definition. It does not describe the timing for every participant. The registry record does not report the median time estimate or its 95% confidence interval, so the magnitude and precision of the primary outcome cannot be read from the record.

Volumetric MRI provides a quantitative way to assess changes in tumor burden, while a stated threshold distinguishes progression from smaller measured changes. As a general matter, the chosen threshold and imaging approach define what counts as an event; they do not by themselves establish whether a treatment caused a difference. The record does not describe how MRI measurements were reviewed, whether assessors were masked, or how measurements and event dates were adjudicated.

Because the study used a cross-over design, the endpoint description allows time to progression to be counted from the start of either phase. The registry record does not explain how time-to-progression observations from the two phases were combined or compared. It also does not report the number of progression events or the primary treatment-effect estimate. The endpoint definition is therefore available, but the numerical primary result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a time-to-event measure. Its event is progression, defined in this trial as at least a 20% increase in the sum of the volumes of all index lesions on volumetric MRI. The time origin is the start of phase A or phase B. The registry lists months as the unit and 8 years as the timeframe. The record does not report the median estimate, the 95% confidence interval, or the number of progression events.

What does a median time-to-event estimate mean?

In general, a median time-to-event estimate marks the time by which half of the analyzed population has experienced the defined event, according to the analysis method. Participants who have not experienced the event by the end of their observation may have incomplete event times. Time-to-event methods can retain information about such participants up to their last observed follow-up rather than treating them as if an event occurred. The registry record does not state which estimator was used, how censoring was defined, or how follow-up ended for individual participants. Therefore, those general features should not be mistaken for a description of the trial’s actual analysis.

How should a confidence interval be read?

In general, a confidence interval expresses uncertainty around an estimated quantity. A 95% confidence interval is a method-based range that reflects the precision of the estimate under the assumptions of the analysis. It is not a guarantee that the true value lies within a particular interval. In this trial, the registry names a 95% confidence interval as the dispersion measure for the primary endpoint, but does not report its bounds. Without those bounds and the estimate they accompany, readers cannot judge the precision of the primary result.

What does a hazard ratio describe?

In general, a hazard ratio compares the rate at which events occur over time between groups, under the model used. It is not a direct comparison of median times, and its interpretation depends on the model and analysis population. The registry record indicates that sponsor-reported hazard ratios are the basis for time-to-event sample-size illustrations, but no hazard-ratio values are reported in the record. No treatment effect can therefore be derived from that note. The registry record also does not state the model used for any primary hazard-ratio analysis.

Why does the cross-over structure matter?

In a cross-over trial, treatment order is part of the design: participants receive both treatments in different sequences. General statistical considerations include differences between periods, changes in participants over time, and possible persistence of an earlier treatment’s effect into a later period. A suitable analysis may need to account for sequence and period, depending on the design and outcome. The registry record does not report whether such effects were tested, what analysis was used, or whether a washout interval was included. These are questions about the reporting available, not evidence that a particular problem occurred.

The record classifies the study as randomized and cross-over, and describes one sequence as tipifarnib followed by placebo and the other as placebo followed by tipifarnib. Randomization can help balance participant characteristics across assigned sequences in general, but it does not eliminate all uncertainty or resolve incomplete follow-up. The method of randomization and allocation concealment is not reported in the registry record.

What do the planning illustrations represent?

Sample-size illustrations based on an observed effect are planning calculations, not observed power and not a new result from the trial. The stated assumptions use a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is described as a fraction of the observed effect. For time-to-event outcomes, the illustrations count total events; for other outcomes, they express participants per arm. The numerical illustrations are not reported in the registry record. They should not be read as the trial’s original design justification, which is also not reported.

In general, a planning calculation depends on the target effect, variability or event rate, significance threshold, and power target. Changing the assumed effect changes the sample size required by the calculation. An illustration based on an observed effect is especially dependent on that estimate and should not be interpreted as proof that the completed study had a particular probability of detecting an effect. The registry record does not report the original sample-size rationale or the assumptions used when the trial was designed.

Finally, the study lists five outcome measures and three analyses, but the registry record does not provide a complete statistical analysis plan. It does not specify the estimator for the median, how confidence intervals were formed, how missing observations were treated, whether tests were adjusted for multiple comparisons, or how the cross-over periods were included. Those omissions limit independent assessment of the analytical choices. General statistical explanations clarify what the named methods mean, but cannot fill in methods that are not reported for this trial.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and three analyses. It names quality of life as a secondary outcome and identifies median time to progression as the primary endpoint. The other outcome measures and the full set of analyses are not reported in the registry record. The record does not state whether the analyses correspond to separate outcomes, treatment periods, or other comparisons.

Multiplicity arises when several outcomes or comparisons are examined. In general, conducting multiple statistical tests can increase the chance that at least one result appears noteworthy by chance. A prespecified hierarchy or adjustment can help define how multiple results should be interpreted. The registry record does not report a multiplicity strategy, testing hierarchy, or adjusted results. This absence does not establish that no such procedure was used; it means the procedure is not reported in the registry record.

The record also does not explain how missing outcome measurements, incomplete follow-up, withdrawals, or censoring were handled. These details are important for a time-to-event endpoint because the analysis depends on when participants were last observed and whether progression was recorded. No missing-data method or sensitivity analysis is reported in the registry record.

The primary-outcome population description gives 62 phase A starters, 2 ineligible participants, and 43 phase B starters. It does not give a complete account of participants by randomized sequence or state which participants were included in each analysis. The registry record does not report whether analyses followed the assigned sequence, used only participants completing both periods, or used another population definition. These gaps limit assessment of how the reported population relates to the randomized participants.

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: neutropenia (6.7%), diarrhea (1.7%), hallucinations (1.7%), hypofibrinogenemia (1.7%), rash (1.7%).

The safety group is labeled “Tipifarnib & Placebo,” with 60 participants at risk for serious adverse events and 9 affected. The record also lists 60 at risk for other adverse events and 59 affected. It reports 0 deaths. These are counts for the combined group, not separate estimates for tipifarnib and placebo or for each cross-over period.

The listed serious adverse-event terms include neutropenia at 6.7%, and diarrhea, hallucinations, hypofibrinogenemia, rash, and SGOT (AST), each at 1.7%. These percentages are quoted as recorded. They describe the listed terms and do not show how risk differed between treatment periods. The registry record does not provide event timing, severity grades, duration, or a treatment-specific attribution for these terms.

In general, an adverse-event count indicates how many participants were reported as affected under the stated definition; it does not by itself establish that treatment caused an event. A combined safety group in a cross-over study also does not allow a direct comparison of adverse-event rates between the two treatments. The posted counts should therefore be read as descriptive safety information rather than as a comparative treatment-effect estimate.

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

The record establishes that a randomized, cross-over phase II study of tipifarnib and placebo was completed in participants with neurofibromatosis type 1 and progressive plexiform neurofibromas. It defines the primary outcome as median time to progression and specifies an MRI-based progression threshold. It also lists selected safety counts and quality of life as a secondary outcome. These details describe what the study set out to evaluate and some of what was recorded.

The primary numerical result is not reported in the registry record. The median time to progression, its 95% confidence interval, a treatment comparison, and the number of progression events are absent. Therefore, the record does not establish the size or direction of any difference in progression timing, nor how precise an estimate would be. The absence of a reported estimate is not evidence that the treatments had identical outcomes; it leaves the primary comparison unquantified in this record.

The cross-over design means the two treatment sequences and treatment periods are relevant to interpretation. The registry record does not explain how the primary analysis addressed sequence, period, or possible persistence of treatment effects across periods. Nor does it fully describe the analysis population, missing-data handling, or the methods used to calculate the endpoint estimate. Those limits prevent a complete statistical appraisal from the recorded information alone.

The safety figures indicate that the record lists 9 serious adverse-event-affected participants among 60 at risk, 59 with other adverse events among 60 at risk, and 0 deaths in the combined group. The listed serious-event terms provide additional description, but the record does not separate them by treatment. They should not be interpreted as a comparative estimate of treatment-specific safety.

In general, a trial’s rationale, design, endpoint definition, and observed results answer different questions. The biological rationale explains why a drug might be studied; the randomized design describes how treatment sequences were assigned; and outcome estimates quantify what was observed. Here, the rationale and design are described, while the primary numerical outcome is not reported in the registry record. No conclusion about clinical benefit or lack of benefit follows from the missing estimate.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining random assignment with a cross-over structure. In general, cross-over designs allow participants to receive treatments in different orders, which can support within-participant comparisons. At the same time, period and sequence effects can matter, and a later period may be influenced by an earlier one. Clear reporting of the analysis is important for understanding how those design features were handled. The registry record does not report those analytical details.

The primary endpoint is also defined in a concrete, quantitative way: progression requires at least a 20% increase in the summed volume of index lesions measured by MRI. That definition makes the event operational for a time-to-event analysis. Yet a well-defined endpoint cannot substitute for a reported estimate. Without the median time, confidence interval, or treatment comparison, readers cannot assess the observed timing or precision of progression.

The record also illustrates why population counts need context. It reports 62 phase A starters, 2 ineligible participants, and 43 phase B starters, but does not provide a complete flow by sequence or a clear analysis population. In a cross-over trial, knowing who contributed data in each period is relevant to understanding how the comparison was constructed.

Safety reporting likewise requires attention to the unit and grouping of the data. The listed figures combine tipifarnib and placebo rather than presenting separate treatment-period estimates. The counts are useful as a record of reported events, but they cannot answer a comparative safety question on their own. Overall, the trial record offers design and endpoint information that help frame the statistical questions, while its missing primary estimate and analysis details limit what can be concluded quantitatively.

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 for statistical interpretation is that it does not report the primary median time-to-progression estimate or its 95% confidence interval. It also does not report a numerical treatment comparison, the number of progression events, or a hazard-ratio value. The endpoint is defined, but its estimated result and precision are not available in the registry record.

The study is described as cross-over, but the record does not explain how the primary analysis used data from the two periods or handled sequence and period effects. It does not state whether a washout interval was used or how possible carry-over was assessed. These are reporting limitations, not grounds to assume that the analysis was inappropriate.

The population description is incomplete for evaluating the analysis. It gives counts for participants who started phase A, those recorded as ineligible, and participants who started phase B, but does not provide full flow by assigned sequence, reasons for not entering phase B, or the population included in each analysis. Missing-data and censoring procedures are also not reported.

The record lists five outcome measures and three analyses, but does not identify all of them or describe how multiplicity was handled. It does not provide a full statistical analysis plan or the trial’s sample-size justification. While planning illustrations are described as based on the observed effect, their numerical values are not reported in the registry record and do not represent the original design rationale.

For safety, the group combines tipifarnib and placebo, so the listed adverse-event figures do not give a treatment-specific comparison. The record also does not provide event timing or detailed severity information for the listed terms. Finally, the official title describes double-blinding, while the registry classification lists single masking; the record does not explain the difference.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas — NCT00021541.
• Registry record last updated 2018-04-17; status last verified 2018-03.
• Results first posted 2012-09-17.
• 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 trial randomized 62 participants to cross-over treatment sequences of tipifarnib and placebo. It studied children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. The primary outcome was median time to progression, defined by an MRI-based increase of at least 20% in the summed volume of index lesions. The registry records an 8 years timeframe and lists a 95% confidence interval as the dispersion measure.

The registry record does not report the primary median estimate, its confidence interval, or a numerical treatment comparison. It lists quality of life as a secondary outcome and reports combined safety figures, including 9 serious adverse-event-affected participants among 60 at risk and 0 deaths. The design is marked cross-over and single-masked, although the official title describes double-blinding. Details of the primary analysis, missing-data handling, multiplicity strategy, and complete analysis populations are not reported in the registry record.