Individualized High Dose Methotrexate to Treat Cancer in Children Who Have a Significant Risk for Side Effects to Methotrexate: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Individualized High Dose Methotrexate to Treat Cancer in Children Who Have a Significant Risk for Side Effects to Methotrexate (NCT02076997), a na na study. The primary outcome is Incidence of Success (Achieving an End Infusion Peripheral Blood Methotrexate Concentration Between 50-80 μM).

2. Clinical Question

3. Trial Design

This completed study evaluated individualized high-dose methotrexate in children and adolescents with cancer who were considered at increased risk of methotrexate side effects. The registry lists Baylor College of Medicine as sponsor and records enrollment as 23. The recorded start date is 2014-01-01, and the primary completion date is 2017-05-30. The study status is completed.

The design is single-group, with no masking. Allocation and phase are recorded as NA. There is no randomized comparator, so the study does not make a direct comparison between an individualized protocol group and a concurrent usual-care group. Usual care is described only as context: the initial ordered methotrexate amount and duration of infusion would not change, while monitoring of blood levels during the first 24 hours could inform adjustment of the final amount received.

The intervention is listed as methotrexate, and the arm description specifies individualized high-dose methotrexate given as a 24-hour infusion. The stated rationale is to avoid methotrexate levels that are too high, which are thought to contribute to side effects. That rationale describes the study's aim, not a demonstrated result.

The registry lists 8 outcome measures and 3 analyses. It does not report a sample-size justification, detailed statistical analysis plan, interim analysis plan, or further design details in the registry record. Those omissions limit what can be concluded about how the study was planned and how its outcomes were analyzed.

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

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 Incidence of Success (Achieving an End Infusion Peripheral Blood Methotrexate Concentration Between 50-80 μM), measured over 1 month.

The primary endpoint is titled as the incidence of success, with success defined as achieving an end-infusion peripheral blood methotrexate concentration between 50-80 μM. Its timeframe is 1 month. This target is used to assess whether the individualized dosing approach reaches the concentration range set out in the study question. The study description links early blood-level monitoring and possible adjustment of the final dose to an aim of avoiding excessively high levels in patients considered at increased risk of side effects.

The registry's outcome fields also characterize the primary measure as a continuous outcome summarized by a mean and standard deviation, with unit uM. That characterization sits alongside the title's incidence-of-success wording, which describes whether a concentration falls within a specified range. The registry record does not explain how these descriptions relate to the analysis or give numerical outcome values. It therefore does not establish whether the posted primary result is a success count, a summary of measured concentrations, or both.

Neither the target range nor a recorded concentration result alone establishes a clinical benefit. The registry record does not report the primary success count or rate, a mean concentration, a standard deviation, or an estimate of uncertainty for this endpoint. The endpoint describes the protocol's concentration target; interpretation of its clinical importance requires evidence beyond the target definition itself.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

A single-group design follows participants receiving the study approach without assigning a concurrent control group. This can describe what was recorded during treatment, but it does not separate the effects of the study approach from other influences on outcomes. Because this study has no randomized comparison, it cannot directly estimate how outcomes would differ under another treatment or monitoring strategy. The registry records allocation as NA and masking as NONE.

What does the primary outcome represent?

The outcome title frames success as an end-infusion concentration falling within a defined range. For an outcome defined this way, an analysis could report the number who meet the target, or a proportion among participants with an evaluable measurement. Those summaries answer a different question from the mean and standard deviation of the measured concentrations, which describe the distribution of a continuous measurement. The registry's outcome fields indicate mean and standard deviation, while its title describes incidence of success. The registry record does not explain this distinction or report values for either form of summary.

In general, a mean describes a distribution's central value, while a standard deviation describes how spread out measurements are around that mean. Neither alone tells how many measurements fall within a target interval. A confidence interval, in general, represents uncertainty around an estimated quantity under the assumptions of the analysis. No primary outcome confidence interval is reported in the registry record, so the precision of the target-attainment estimate cannot be assessed from the posted primary results.

How should the study's design shape interpretation?

Random allocation, when used, can help make groups comparable on average, whereas this record describes a single group with no randomized allocation. A before-and-after or single-group observation is not a substitute for a concurrent comparison: changes may reflect participant characteristics, clinical care, or other factors as well as the intervention. The registry does not report a control arm, and the study description of usual care does not create one. The registry also does not report whether any analysis adjusted for participant characteristics or other factors.

Masking is recorded as NONE. Masking can reduce the influence of knowledge about treatment assignment on some aspects of measurement or assessment; its relevance depends on the outcome and how it is measured. The registry record does not describe masking procedures beyond that entry or explain how outcome measurements were assessed.

What do the planning assumptions mean?

The sample-size illustrations are planning exercises based on the observed effect, not the study's own design. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. These assumptions define hypothetical planning scenarios; they do not describe this single-group study's actual allocation or establish the size of the study's observed effect.

For the illustrations, time-to-event tables use the total number of events, using the Schoenfeld approach, while other illustrations use participants per arm. These are planning quantities, not observed participant counts or evidence that a study had a particular probability of detecting an effect. Sample-size calculations describe what may be needed under assumptions; they are never observed power. The registry record does not report a sample-size justification for the trial itself.

In general, over-dispersion means that outcome variability exceeds what a chosen statistical model assumes. If present, it can make uncertainty estimates from a model too narrow unless accounted for. The registry record does not report whether over-dispersion was assessed, and the primary outcome results needed to assess its relevance are not reported. This is a general statistical consideration, not a finding about this study.

The registry lists 3 analyses, but does not describe their methods, covariate adjustments, or how they relate to the primary endpoint. The record also does not provide an analysis plan, test statistics, or p-values for the primary outcome. Without those details and the actual outcome estimates, an independent assessment of the analysis cannot be made.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Individualized High Dose Methotrexate")
n   <- c(22)
m   <- c(57)
sp  <- c(14)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Individualized High Dose Methotrexate  22  57.000  14.000  50.793  63.207

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and 3 analyses. When a study evaluates multiple outcomes or carries out multiple analyses, the chance of at least one apparently unusual result can increase if no allowance is made for repeated testing. Statistical approaches can address this issue, but the registry record does not report whether any multiplicity adjustment was planned or used. The number of listed outcomes and analyses alone does not establish that a particular adjustment was necessary or absent.

The primary outcome is identified by title, but the record does not report how secondary outcomes were prioritized or whether the analyses were prespecified. Secondary outcomes include incidence of >Grade 3 nephrotoxicity, neurotoxicity, mucositis, hepatoxicity, and myelosuppression. Numerical results for these outcomes are not included in the registry record summarized in the study details.

Missing-data handling is not reported in the registry record. The record does not state whether all enrolled participants contributed primary endpoint measurements, how missing or unevaluable concentrations were handled, or whether any sensitivity analyses were conducted. It also does not describe analysis populations, such as which participants were included in each outcome analysis. These omissions matter because the interpretation of an endpoint can depend on who was measured and how unavailable observations were treated.

The enrollment entry is 23, while the adverse-event fields list 22 participants at risk. The registry record does not explain the different counts. It would not be appropriate to assume why they differ or to infer an analysis population from them.

12. 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 5% reporting threshold.

The registry lists the Individualized High Dose Methotrexate group with 22 participants at risk for serious adverse events and 0 affected. It also lists 22 at risk for other adverse events and 0 affected, with 0 deaths. These are the recorded counts for the fields shown in the registry record; they are not rates calculated.

A zero recorded count means no affected participants are listed for that category in the registry entry. It does not establish that no events occurred outside what was captured or reported, and it does not demonstrate that the intervention lowered risk. With no concurrent comparator group, the counts cannot quantify a difference in safety relative to another approach. The registry does not list serious adverse event terms, and it does not provide further detail about event definitions or the way the at-risk group was determined.

The enrollment entry is 23, whereas the adverse-event at-risk count is 22. The registry record does not explain that difference, so the safety denominator should be read as recorded rather than reconciled with enrollment. These figures should also be kept separate from the listed secondary outcomes for specific toxicities, for which numerical results are not reported in the registry record.

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

The record establishes that investigators studied individualized high-dose methotrexate in a group of children and adolescents with cancer who were considered at increased risk of side effects. It describes a 24-hour infusion and a method in which blood levels in the first 24 hours could inform adjustment of the final amount received. It also identifies a primary concentration target and records a completed study.

It does not report the numerical primary outcome results. There is no posted count or rate of participants who achieved the end-infusion concentration target, and no reported mean or standard deviation despite the continuous-outcome fields. Without those results, the registry record cannot establish whether the target was reached often, rarely, or with a particular degree of precision.

The single-group design also limits what can be inferred. Even if primary results were available, outcomes in a group receiving the individualized approach would not, on their own, show how outcomes compare with a concurrent alternative. The registry record does not support a causal comparison or a conclusion that this approach prevents toxicity.

The safety counts are similarly limited. The record lists zero affected for serious and other adverse events and zero deaths among the listed at-risk group, but does not provide a comparison group or detailed event descriptions. Those entries should be understood as recorded counts, not proof that risk is absent.

More broadly, a concentration target is a protocol-defined measure, not itself a patient-centered outcome. The registry describes the aim of avoiding excessively high methotrexate levels and associated side effects, but the information reported does not demonstrate that the target translated into fewer toxicities or improved clinical outcomes. The registry record therefore supports description of the study's question and design, while leaving the primary result, its precision, and comparative clinical implications unresolved.

14. Why This Trial Matters Statistically

This study raises a statistical question that is common in dose individualization: how to assess whether monitoring and adjustment bring a measured exposure into a defined target range. The registry makes the target explicit as an end-infusion blood concentration between 50-80 μM. A clearly stated target can make a clinical protocol question concrete, but meaningful interpretation also requires the observed concentration data and a clear account of how success is summarized.

Here, the outcome title describes incidence of success, whereas the registry's outcome fields specify a mean and standard deviation for a continuous measure. Those descriptions point to different summaries, and the record does not explain their relationship. This matters because a mean can conceal how measurements are distributed relative to a target interval. A success count or proportion would directly describe target attainment, while a continuous summary would describe concentration values in another way.

The single-group design is also statistically important. It can document outcomes under the protocol, but without a concurrent comparator it cannot distinguish the protocol's effect from other explanations. The registry's zero adverse-event counts are descriptive and cannot show a reduction in toxicity. The study's stated rationale is not a substitute for comparative evidence.

Finally, missing results and analysis details are not merely administrative gaps: they constrain assessment of effect size, precision, outcome handling, and multiplicity. The registry record lists several outcomes and analyses but does not describe their statistical methods. This makes transparent reporting of the primary estimate and its uncertainty especially important for readers assessing a protocol based on drug-level monitoring.

15. 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 primary limitation for interpreting this record is that numerical primary outcome results are not reported in the registry record. The concentration target is stated, but no success count or rate, mean, standard deviation, or uncertainty estimate is available in the record details. As a result, the key endpoint cannot be quantitatively assessed.

The endpoint description is not fully aligned across the registry fields: the title refers to incidence of success within a target range, while the outcome characteristics specify a mean of a continuous measure with standard deviation. The record does not clarify which summary was analyzed or how the endpoint was defined for analysis. This makes the intended statistical interpretation uncertain.

The design is single-group, has no randomized allocation, and has no concurrent comparator. This limits causal and comparative interpretation, including for safety. Masking is recorded as NONE, and further details on outcome assessment are not reported. The record also does not give the statistical analysis plan, sample-size justification, interim analysis information, missing-data methods, or analysis populations.

Enrollment is recorded as 23, while the serious and other adverse-event fields each list 22 participants at risk. The reason for these different recorded counts is not reported in the registry record. The adverse-event counts do not include serious event terms, and the record does not provide numerical results for the listed toxicity outcomes. These limitations should be kept in view when interpreting the protocol's rationale and the recorded safety entries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Individualized High Dose Methotrexate to Treat Cancer in Children Who Have a Significant Risk for Side Effects to Methotrexate — NCT02076997.
• Registry record last updated 2021-02-24; status last verified 2021-02.
• Results first posted 2021-02-24.
• 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.

19. Record Summary

NCT02076997 is a completed, single-group study sponsored by Baylor College of Medicine. It evaluated individualized high-dose methotrexate in children and adolescents with cancer considered at increased risk of methotrexate side effects. The registry records enrollment as 23 and describes a 24-hour methotrexate infusion, with early blood-level monitoring used to guide possible adjustment of the final amount received.

The primary endpoint concerns achieving an end-infusion peripheral blood methotrexate concentration between 50-80 μM, with a timeframe of 1 month. Numerical primary endpoint results and detailed analysis methods are not reported in the registry record. The safety fields list 22 participants at risk and 0 affected for serious adverse events, 22 at risk and 0 affected for other adverse events, and 0 deaths. No concurrent comparator is reported, so the design supports descriptive interpretation rather than a direct treatment comparison.