Glucarpidase Effect on Severe Delayed HDM-clearance in Children Treated With High-dose Mtx in ALL: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Glucarpidase Effect on Severe Delayed HDM-clearance in Children Treated With High-dose Mtx in ALL (NCT01305655), a na phase 3 study. The primary outcome is Number of Participants With Adverse Event to HD-MTX Treatment in NOPHO ALL-2008 as a Measure of Toxic Mtx Concentrations in Blood, Nephrotoxicity, Hepatotoxicity, Mucositis, MTX Elimination Time and Permanent Kidney Damage..

2. Clinical Question

3. Trial Design

The registry lists this study as phase 3 and single-group, with enrollment of 47. The condition is acute lymphoblastic leukemia, and the intervention is glucarpidase. Allocation is marked NA and masking is listed as none. These design details matter for interpretation: the record describes treatment in a glucarpidase arm, not a randomized comparison between glucarpidase and a control treatment.

The arm description places glucarpidase within the NOPHO ALL-2008 protocol. Patients with delayed methotrexate elimination during high-dose methotrexate treatment were to receive glucarpidase at 50 ie/kg within 60 hours from the start of methotrexate treatment. The primary outcome description adds that use depended on predefined toxic methotrexate values at defined time points and/or decreased renal function. Further operational details about these triggers are not reported in the registry record.

The record states that a total of 47 patients out of 1286 ALL-patients included in the protocol were treated with glucarpidase, reported as 3.7%. This describes the proportion as recorded; it does not establish how patients were selected into treatment beyond the stated clinical triggers. The registry status is completed. The listed start is 2008-07 and primary completion is 2014-12.

The primary outcome timeframe is 6 years 6 months. The registry record does not specify a comparator, a separate control cohort, or a randomized allocation procedure. Nor does it report a statistical analysis plan or an analysis population. As a result, the design information supports descriptive interpretation of the treated group, but does not by itself establish what would have happened to comparable patients without glucarpidase.

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 Number of Participants With Adverse Event to HD-MTX Treatment in NOPHO ALL-2008 as a Measure of Toxic Mtx Concentrations in Blood, Nephrotoxicity, Hepatotoxicity, Mucositis, MTX Elimination Time and Permanent Kidney Damage., measured over 6 years 6 months.

The primary endpoint is described as the number of participants with an adverse event to high-dose methotrexate treatment in NOPHO ALL-2008. The outcome title names toxic methotrexate concentrations in blood, nephrotoxicity, hepatotoxicity, mucositis, methotrexate elimination time and permanent kidney damage. The record also says glucarpidase was used in case of predefined toxic methotrexate values at defined time points and/or in combination with decreased renal function. These details connect the endpoint to both methotrexate exposure and potential organ or treatment-related effects.

Counting participants with an event is a binary-outcome approach: each participant is classified according to whether the event definition is met. In general, this can communicate how frequently an event was recorded in the group, but the interpretation depends on precise definitions, time windows and ascertainment procedures. Those operational definitions are not reported in the registry record beyond the descriptions above.

The endpoint title covers several types of outcomes. They may not have the same clinical meaning or measurement method, so a single participant count would not describe the detail of each component unless component-specific results are also reported. The numerical primary-outcome result and component-level counts are not reported in the registry record. The adverse-event fields separately list zero affected for serious and other adverse events; those entries should not be treated as a complete numerical report of every component named in the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design estimate?

In general, a single-group study describes outcomes among people who received the intervention under the recorded conditions. It can document treatment use, event counts and other observed characteristics. Without a comparison group, it does not directly estimate the difference between outcomes under glucarpidase and outcomes under an alternative. In this record, allocation is marked NA and the model is single-group; the posted results therefore require descriptive rather than comparative interpretation.

The treated group is also defined in relation to delayed methotrexate elimination and clinical triggers: the arm description refers to delayed elimination, while the outcome description refers to predefined toxic values at defined time points and/or decreased renal function. In general, treatment triggered by clinical status creates a selected group whose characteristics may differ from patients who were not treated. The registry record does not report the characteristics of untreated patients or a controlled comparison that would address those differences.

How should binary event counts be read?

The primary outcome is framed as the number of participants with an event. In general, a binary outcome records whether each participant meets an event definition during a specified period. A count can be informative, but its meaning depends on the denominator, the observation window, definitions and completeness of follow-up. The adverse-event fields list 47 at risk and 0 affected in each of the serious and other categories. The primary outcome's numerical count is not reported in the registry record, so the adverse-event entries should not be substituted for it.

In general, when event counts are small or zero, the observed data alone may leave substantial uncertainty about the underlying event frequency. A confidence interval is a statistical range expressing uncertainty around an estimate under a specified method and assumptions; it is not a guarantee that the true value lies within a particular interval. No confidence interval or interval method is reported in the registry record. No new interval can be inferred from the posted counts without adding an analysis that is not reported there.

Why does the missing comparator matter?

In a randomized comparison, random allocation is intended to make treatment groups comparable on average, supporting estimation of a treatment contrast. General causal interpretation still depends on how outcomes are measured and how missing information is handled. Here, the registry identifies no randomized comparison and lists no comparator arm. Thus, the serious and other adverse-event counts describe the recorded glucarpidase group only. They do not show what event counts would have been in the same kind of patients without glucarpidase.

Even a comparison with an external group would require care: differences in disease status, methotrexate exposure, kidney function, event monitoring or treatment eligibility could affect outcomes. No external comparison is described in the registry record. The account of treatment triggers helps explain the context for administration, but does not supply the information needed to adjust for such differences.

What can planning illustrations tell readers?

General sample-size planning uses assumptions about the outcome, treatment contrast, significance level, allocation and statistical method to illustrate how much information a future comparison might require. The planning description associated with this record specifies a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect set as a stated fraction of the observed effect. It also distinguishes total event counts for time-to-event outcomes from participants per arm for other outcomes.

Such calculations are planning illustrations, not findings from the treated group and not observed power. They do not establish that the trial used those assumptions when it was designed. The registry record does not report a sample-size justification, an original statistical plan, or calculated planning results as part of the trial's own design. No treatment contrast can be recovered from the single-group adverse-event counts. Since the primary outcome result is not reported, a planning illustration based on an observed primary effect cannot be interpreted as evidence about the trial's precision or efficacy.

What is not documented?

The registry reports no analyses. Statistical tests, model specifications, confidence intervals, covariate adjustments, interim analyses and prespecified decision rules are not reported in the registry record. General statistical methods can explain what such procedures would do, but their use cannot be assumed for this study. In particular, a lack of reported analysis is not evidence that an unreported method was or was not used.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Glucarpidase Arm")
n      <- c(47)
events <- c(47)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Glucarpidase Arm  47  47  100.0  92.5  100.0  92.4  100.0  92.6  99.9

11. Multiplicity, Missing Data and Analysis Populations

The primary outcome title covers several types of events and measures, including toxic methotrexate concentrations, nephrotoxicity, hepatotoxicity, mucositis, methotrexate elimination time and permanent kidney damage. When a study evaluates multiple outcomes or components, general statistical practice may require a prespecified approach to distinguish the primary question from additional analyses and to address the increased chance of apparently notable findings across repeated tests. A multiplicity plan is not reported in the registry record.

The record identifies one primary outcome measure, but it does not report component-specific outcome results, a hierarchy among the listed measures, or whether any secondary outcomes were analyzed. It reports no analyses. The statistical analysis plan, hypothesis tests and adjustment methods are not reported in the registry record. It is therefore not possible to determine how multiple outcomes, if analyzed, were handled.

Missing-data handling is also not reported in the registry record. The record does not describe loss to follow-up, missing outcome values, exclusions from analysis or imputation methods. The listed adverse-event fields indicate 47 at risk, but the record does not explain whether every participant had complete observation for every endpoint throughout the stated timeframe. An at-risk count alone does not establish complete outcome ascertainment.

The analysis population is not reported in the registry record. The record does not state whether analyses used all treated participants, participants meeting a defined eligibility set, or another population. It also does not describe how deviations from the treatment timing or dose were handled. These omissions limit assessment of the population to which the outcome counts apply and of whether any exclusions could have altered the results.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The serious adverse-event fields list 47 participants at risk and 0 affected in the glucarpidase arm. The other adverse-event fields likewise list 47 at risk and 0 affected. These are the recorded figures for the respective categories; they are not a detailed accounting of all outcomes named in the primary endpoint.

A recorded zero should be read as no affected participants listed in that category, rather than as proof that the event is impossible or that all relevant events were excluded. In general, interpretation of safety counts depends on event definitions, observation time and how completely events were collected. The registry lists a primary-outcome timeframe of 6 years 6 months, but does not explain the specific follow-up or ascertainment procedures for the adverse-event fields.

The death field is null, so a death count is not reported in the registry record. The record also does not provide event narratives, severity details beyond the serious/other categories, timing, attribution, or component-specific safety counts. The absence of listed affected participants in these categories cannot establish a comparative safety profile because no comparator group is recorded.

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

The registry record documents a single-group study of glucarpidase in the setting of high-dose methotrexate treatment for acute lymphoblastic leukemia. It describes a protocol context in which treatment was used for delayed methotrexate elimination and predefined toxic values and/or decreased renal function. The recorded arm description specifies 50 ie/kg within 60 hours from the start of methotrexate treatment. These are descriptions of the protocol context, not a comparative estimate of treatment effect.

The posted adverse-event figures list 0 affected for serious events and 0 affected for other events, with 47 at risk in each category. Those figures describe the entries in the registry record. They do not establish that no other clinically relevant events occurred, because the record does not provide complete endpoint-specific counts, event definitions or ascertainment details. Nor do they answer the full primary-outcome question: a numerical result for the primary endpoint is not reported in the registry record.

The record states that 47 patients out of 1286 ALL-patients included in the protocol received glucarpidase, reported as 3.7%. This gives context for how often glucarpidase was used in the protocol population as recorded. It does not compare outcomes for those treated with outcomes for those not treated, and it does not show that the treated group was interchangeable with untreated patients.

Because the design is single-group, allocation is NA and no comparator is identified, the data do not estimate a causal effect. The registry record does not report an analysis plan, treatment-effect estimate, confidence interval or statistical test. Consequently, the listed counts should not be described as proof that glucarpidase works or does not work, nor as evidence of relative safety versus another approach. They are limited descriptive observations, and important details needed to assess precision and completeness are not reported in the registry record.

14. Why This Trial Matters Statistically

This record is statistically informative because it illustrates the difference between documenting a treatment pathway and estimating a treatment effect. Glucarpidase was used in a defined clinical context involving delayed methotrexate elimination and/or predefined toxic values or decreased renal function. The registry also reports how many patients in the wider protocol population received it. Such information helps describe the setting in which the intervention was used.

At the same time, treatment triggered by clinical circumstances does not create a direct comparison. Patients who received glucarpidase were selected under the stated conditions, and the record does not provide outcomes for a comparable untreated group. A descriptive count can therefore answer what was recorded in the treated group, but not what would have happened to those patients under another treatment strategy. This is a central distinction in clinical-trial interpretation, especially when the design is single-group.

The record also illustrates why outcome definition and reporting detail matter. The primary endpoint title spans several clinical and treatment-related measures, while the adverse-event fields separately list serious and other categories. Without component-level results and clear ascertainment details, readers cannot determine whether the adverse-event fields capture each aspect of the primary question. The primary numerical outcome is not reported in the registry record.

Finally, a zero recorded count is a useful observation but not a complete account of uncertainty. Without confidence intervals, analysis methods, a documented analysis population or missing-data information, the precision and completeness of these safety entries cannot be fully assessed. The record is valuable as a description of protocol use and recorded adverse-event counts, while its design and reporting limit comparative and causal conclusions.

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 most important trial-specific limitation is the absence of a comparator. The record lists a single-group model, allocation marked NA and masking as none. Therefore, the observed adverse-event entries cannot be contrasted with outcomes under no glucarpidase or another treatment. The design does not establish a treatment effect.

The primary outcome is described broadly, covering toxic methotrexate concentrations, nephrotoxicity, hepatotoxicity, mucositis, methotrexate elimination time and permanent kidney damage. However, a primary-outcome count and component-specific results are not reported in the registry record. The separate adverse-event figures cannot be assumed to summarize all these outcomes.

Further details needed to assess the results are also not reported in the registry record: operational event definitions, the ascertainment process, follow-up completeness, missing-data handling, analysis population and statistical analysis plan. The record does not report confidence intervals or statistical tests. The death field is null, rather than a reported count.

The treatment criteria indicate that glucarpidase use was related to delayed methotrexate elimination and/or predefined toxic values or decreased renal function. This means the group is defined by treatment-related clinical circumstances, but the record does not provide enough information to characterize those circumstances or compare treated participants with untreated patients. Although enrollment is 47 and the record states that 47 patients were treated, details of the eligible population and any exclusions are not reported. These limits restrict interpretation to the recorded descriptive information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Glucarpidase Effect on Severe Delayed HDM-clearance in Children Treated With High-dose Mtx in ALL — NCT01305655.
• Registry record last updated 2018-09-28; status last verified 2018-08.
• Results first posted 2017-02-03.
• 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

The registry record describes a completed phase 3, single-group study of glucarpidase in children and adolescents with acute lymphoblastic leukemia treated with high-dose methotrexate. Enrollment is 47. The intervention was used for delayed methotrexate elimination and predefined toxic values and/or decreased renal function; the arm description specifies 50 ie/kg within 60 hours from the start of methotrexate treatment.

The record states that 47 patients out of 1286 ALL-patients included in the protocol were treated with glucarpidase, reported as 3.7%. The primary endpoint concerns participants with adverse events and names several toxicity and treatment-related measures, but its numerical result is not reported in the registry record. The adverse-event entries list 0 affected for serious events and 0 for other events, with 47 at risk in each category. No comparator, statistical analysis, confidence interval, or analysis population is reported.