NOPHO ALL-2008 Pilot Study on Consolidation Therapy for Children and Adolescents With Acute Lymphoblastic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for NOPHO ALL-2008 Pilot Study on Consolidation Therapy for Children and Adolescents With Acute Lymphoblastic Leukemia (NCT00548431), a na phase 2 study. The primary outcome is Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported.

2. Clinical Question

The study was designed as a pharmacokinetic-pharmacodynamic pilot. Its stated purpose was to explore toxicity and antileukemic response during the initial 3 months of individualized therapy, and to assess the feasibility of combining dose-titrated 6-mercaptopurine with continuous PEG-asparaginase and interspersed high-dose methotrexate. The posted primary outcome addresses toxicity through counts of participants with reported events. The record does not provide a comparative estimate for antileukemic response in the primary outcome results.

The main statistical question is therefore descriptive: what event counts were recorded in this treatment group, and how narrowly or broadly should those counts be interpreted? Without a control group, the event counts cannot establish whether the regimen caused more or fewer events than another regimen, or whether individualized titration changed risk. The results also do not, by themselves, quantify the balance between toxicity and antileukemic response. That broader assessment would require outcome information and a design suited to the comparison being asked.

3. Trial Design

This was a Phase II, single-group pilot study registered as NCT00548431. The registry lists Copenhagen University Hospital, Rigshospitalet as the sponsor, a start date of 2007-12, primary completion in 2009-01, and a completed status. Allocation is recorded as NA and masking as none. These design features mean the results describe participants receiving the study regimen; they do not provide a randomized comparison against a separate control group.

The study concerned consolidation treatment for children and adolescents with acute lymphoblastic leukemia, with the brief description also referring to children and young adults. The planned treatment combined individualized 6-mercaptopurine dose increments with high-dose methotrexate and PEG-asparaginase. The arm description states that all patients received daily basic 6-mercaptopurine at 25 mg/m^2, high-dose methotrexate every 3rd week, and PEG-asparaginase every 14th day. It describes increasing 6-mercaptopurine 2 weeks after each high-dose methotrexate treatment if myelotoxicity had been acceptable. The brief description refers to the initial 3 months of treatment and to high-dose methotrexate at 5 g/m^2; the arm description states 3 times HDM in total.

The primary outcome is a count of participants with serious adverse events or adverse events, reported over 3 months (79 days). The registry lists 38 participants at risk for both the serious-event and other-event counts. Secondary outcomes concern incorporation of 6-thioguanine nucleotides into leukocyte DNA and development of asparaginase antibody production. The posted record does not report a randomized allocation procedure, a masking procedure, or a concurrent comparator. It also does not report details of a statistical analysis plan or a sample-size justification.

Because the design is single-group, its useful scope is chiefly descriptive and exploratory. It can document event counts during the regimen and inform questions about feasibility, but it cannot separate treatment-associated events from events that might have occurred under another treatment or without the regimen. Nor does the design support a causal comparison of dose-titration strategies.

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 Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported, measured over 3 months ( 79 days ).

The primary endpoint counts participants reported with serious adverse events or adverse events during 3 months (79 days). The registry labels the unit as participants and the outcome parameter as a number. Its description connects the count to participants following protocol treatment for the full consolidation therapy, during an effort to titrate 6-mercaptopurine individually to the highest tolerable level.

Counting participants gives a direct summary of how many people in the treatment group had reported events. It is distinct from counting the total number of event episodes: a participant with more than one event may still contribute to a participant count, depending on the outcome definitions and reporting rules. Those detailed rules, including how repeated events or overlap between event categories were handled, are not reported in the registry record. The serious-event count and the count for other adverse events should therefore be read as separate reported summaries, not assumed to be mutually exclusive categories.

Safety counts are relevant to a pilot whose stated aim includes exploring toxicity and the feasibility of a drug combination. They provide a description of observed events during the specified treatment period. They do not, by themselves, show whether the regimen caused an event or how its event frequency compares with an alternative. The registry's primary outcome is a count; it does not present a comparative effect estimate or an uncertainty interval for that comparison. The record also does not give a formal definition of the serious-event criteria or additional endpoint-adjudication details.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports event counts rather than a treatment-effect estimate. Understanding what those counts can say begins with the outcome's unit: participants. A participant count records how many people were reported to have an event category; it is not necessarily a count of every event episode. If an individual experiences repeated events, an event-level total could differ from a participant-level count. The registry does not report rules for repeat events or for overlap between the serious and other adverse-event categories, so those details should not be inferred from the counts.

What does a single-group design permit?

In a single-group study, the observed outcomes describe participants who received the study regimen. A treatment comparison ordinarily needs a reference group or another suitable design-based contrast. Since this record has no separate control group and records allocation as NA, it does not estimate a between-group difference. The reported numbers cannot show whether event frequency was higher or lower than it would have been under another regimen. They also cannot establish that a particular drug in the combination caused an event.

This distinction is not a technicality. Treatment was a combination involving 6-mercaptopurine, high-dose methotrexate, and PEG-asparaginase, with dose titration based on acceptability of myelotoxicity. A descriptive result observed during that combination does not isolate the contribution of each component. The registry record does not describe a design or analysis that separates these effects.

How should event counts and percentages be read?

The primary outcome reports participant counts, while the serious-event terms are accompanied by percentages. Counts convey the number of participants reported in an outcome category. Percentages can make the relative size of listed terms easier to interpret, but they do not add information about timing, recurrence, duration, or clinical course. The record identifies neutropenic fever, Hypoglycemia, pancreatitis, and PRES (Posterior Reversible Encephalopathy Syndrome) among the top serious terms. It does not give a full event listing or clarify the denominator and event-counting convention for each listed percentage. Those percentages should therefore be described as the registry's reported values, without assuming an unstated calculation method.

A percentage is not a measure of uncertainty. For that, statistical reporting often uses a confidence interval. In general, a confidence interval expresses the precision of an estimate under the statistical method used; a wider interval indicates less precision, while a narrower interval indicates more precision. The registry record does not provide confidence intervals for these adverse-event results. It is therefore not possible to use the posted figures to quantify their statistical precision with an interval.

Why does the comparator matter?

General statistical principle: a comparison helps distinguish an outcome associated with a treatment strategy from the background frequency of that outcome in a relevant population. Random allocation can support a fair comparison by limiting systematic differences between treatment groups, although it does not remove every source of uncertainty. This study is not described as randomized and has no like-for-like control group. Consequently, the counts are a description of events under the regimen, not an estimate of a comparative treatment effect.

The single-group design also affects interpretation of safety. Some adverse events may arise from the disease, concurrent treatment, or other causes. Without a comparator or a causal analysis reported in the registry, the counts cannot distinguish these possibilities. The term “reported” is important: the data are the registry's recorded results, not a complete causal attribution for each event.

What role do endpoint definitions play?

Reliable interpretation depends on knowing how outcomes were defined and collected. For example, the registry would need to specify which criteria qualified an event as serious, how event reports were reviewed, and how follow-up was handled to support a detailed assessment. Such operational definitions and procedures are not reported in the registry record. The primary outcome title combines serious adverse events or adverse events, while the results are presented as a serious-event count and a count of other adverse events. The available description supports treating those as distinct reported categories, but not assuming that they are exclusive or that each participant could contribute only once.

The timeframe is stated as 3 months (79 days). A fixed observation window can help define what the count covers, but the record does not say whether every participant had complete observation for that period or how missing follow-up was handled. That matters because an incomplete observation period can reduce the opportunity to record events. No conclusion about the completeness of follow-up should be drawn from the event counts alone.

What can be concluded from the statistical reporting?

The posted primary results allow a descriptive statement of the number of participants recorded with serious and other adverse events. They do not include a reported inferential test, a confidence interval, or an adjusted analysis for this endpoint. The registry lists 0 analyses, but the statistical plan and any additional analytic details are not reported in the registry record. Absence of a listed analysis should not be converted into an assumption about what investigators did outside the record.

General statistical principle: over-dispersion is relevant when event counts vary more than a simple probability model expects, often because some participants experience multiple events or participants differ in their underlying risk. An analysis of total event counts may need methods that account for such variation. Here, the primary outcome is a participant count, and no event-level statistical model is reported; therefore, no claim about over-dispersion or a model adjustment is warranted. The key practical point is to keep the statistical question aligned with the reported measure: participant counts describe the observed group, while comparative and model-based conclusions require information and analyses not reported in this record.

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("6-mercaptopurine")
n      <- c(38)
events <- c(26)
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  6-mercaptopurine  38  26  68.4  51.3  82.5  52.5  80.9  52.4  80.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two secondary outcomes: incorporation of 6-thioguanine nucleotides into leukocyte DNA and development of asparaginase antibody production. Numerical results for these outcomes are not reported in the registry record. It also lists 0 analyses. The record does not describe a statistical analysis plan, identify a prespecified testing hierarchy, or report whether any adjustment for multiple comparisons was planned. It would therefore be inappropriate to infer how multiplicity was handled or to treat unreported secondary results as evidence of no effect.

Multiplicity matters in general when several outcomes, time points, subgroups, or statistical tests are examined. Repeated testing can increase the chance of finding an apparently notable result by chance if the analysis does not account for the set of comparisons. Whether that concern applies to a particular analysis depends on what was planned and conducted; those details are not reported in the registry record. The registry's count of 0 analyses does not provide a full statistical plan or establish that no analyses were performed beyond those listed.

The primary endpoint is a participant count over 3 months (79 days). The record does not report missing-data rules, completeness of follow-up, how participants who did not follow treatment fully were handled, or the analysis population used for the posted counts. Although the endpoint description refers to participants following protocol treatment for the full consolidation therapy, it does not specify how that condition was applied in analysis. These missing details make it difficult to judge whether the counts represent all enrolled participants, participants who received treatment, or a defined subset. The statistical consequences of missing or incomplete outcome information cannot be assessed from the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutropenic fever (57.9%), hypoglycemia (5.3%), pancreatitis (2.6%), pres (posterior reversible encephalopathy syndrome) (2.6%).

The serious adverse-event result is 26 participants, with 38 at risk; the other adverse-event result is 23 participants, also with 38 at risk. These are participant counts, not necessarily event totals. The registry does not say whether a participant could be represented in both categories, so the counts should not be added or treated as a partition of the group.

The listed top serious-event terms are neutropenic fever at 57.9%, Hypoglycemia at 5.3%, pancreatitis at 2.6%, and PRES (Posterior Reversible Encephalopathy Syndrome) at 2.6%. The record does not clarify the denominator or event-counting method for these term percentages, or whether the list is exhaustive. Read them as reported descriptions, not as a complete event inventory or as comparative risks.

These figures describe reported safety events during the specified treatment period. They do not establish that the regimen caused each event, and there is no control group for comparison. Deaths are not reported in the registry record. The registry also does not provide event timing, duration, recurrence, grading criteria, or details on follow-up completeness. Those limitations restrict what can be concluded about the pattern and precision of safety outcomes.

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

The results document reported adverse-event counts during a pilot study of individualized 6-mercaptopurine treatment combined with high-dose methotrexate and PEG-asparaginase. Specifically, the registry records 26 participants with serious adverse events and 23 with other adverse events, with 38 at risk in each category. It also reports several top serious-event terms and their percentages. This is useful descriptive information about the experience recorded for the study group during 3 months (79 days).

The results do not show how those counts compare with another treatment approach. Because the study has a single group and no randomized comparator, they cannot establish whether the regimen increased or reduced adverse events relative to another strategy. They also cannot identify which component of the combination contributed to any event or establish a causal relationship for individual events. The event categories may overlap, and the record does not specify the relevant event-counting rules.

The findings also do not settle the study's broader questions about antileukemic response or feasibility. The stated purpose included exploring toxicity and antileukemic response, and the listed secondary outcomes concern biomarker incorporation and antibody production. Their results are not reported in the registry record. The adverse-event figures alone cannot represent the full benefit-risk profile or establish how effectively treatment achieved its intended disease-related aims.

Statistical precision is limited by the type of information posted. The registry does not report confidence intervals or a comparative analysis for the primary outcome. It also does not report how missing observations, treatment discontinuations, or deviations affected the analysis population. A count should therefore be interpreted as the recorded result for this study, not as a highly precise estimate of event frequency in other populations or treatment settings.

The appropriate conclusion is narrow: the record reports these safety counts and serious-event terms for participants in a single-group pilot. Wider claims about causal effects, comparative safety, efficacy, or generalizability require evidence not reported in this record.

14. Why This Trial Matters Statistically

This study matters statistically because its treatment question is exploratory and its design is single-group. The regimen combined individualized 6-mercaptopurine titration with high-dose methotrexate and PEG-asparaginase, while the primary outcome recorded participant counts with reported adverse events. Such descriptive data can document the safety experience during a pilot and help define questions for later evaluation. The data have a more limited role in estimating comparative effects because no control group is present.

The distinction between a descriptive count and a causal comparison is especially important for combination treatment. An event occurring during treatment is not, solely on that basis, attributable to one drug or to the titration strategy. A comparator and clear outcome definitions would be needed to assess whether observed event frequencies differ from a relevant alternative and how that difference should be interpreted. Neither a comparative estimate nor detailed event-attribution methods are reported in the registry record.

The pilot also illustrates why endpoint and follow-up definitions matter. The primary result is a count of participants over 3 months (79 days), while the record does not describe handling of repeated events, overlap between categories, missing outcomes, or the analysis population. Those details affect whether readers can reproduce the endpoint interpretation or assess its precision. The absence of confidence intervals further means that statistical uncertainty is not quantified in the posted primary results.

As a registered Phase II study completed in 2009-01, the record preserves an account of the intended combination and the safety counts reported for it. Its statistical contribution is descriptive rather than comparative. The findings can inform understanding of what was recorded in this pilot, but the registry record does not support a treatment-effect claim or a complete assessment of the study's stated response and feasibility questions.

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 main limitation is the single-group design. With allocation recorded as NA and no control group, the study cannot provide a randomized comparison or estimate a contrast between treatment strategies. Its event counts are specific to participants receiving the regimen and cannot establish how outcomes would differ under another approach.

The regimen itself was a combination, including 6-mercaptopurine, high-dose methotrexate, and PEG-asparaginase. The record describes individualized dose increases based on acceptable myelotoxicity, but does not report an analysis separating the contribution of each treatment component. Events recorded during the combination cannot be attributed to a particular drug from these results alone.

Outcome-reporting detail is limited. The registry does not report formal definitions for serious events, procedures for event review, repeated-event handling, or whether participants could be counted in both event categories. The primary outcome timeframe is 3 months (79 days), but completeness of follow-up and handling of missing data are not reported. The analysis population and the treatment of participants who did not complete protocol treatment are also not reported in the registry record.

The primary results are counts without reported confidence intervals or a comparative statistical analysis. The registry does not provide a statistical analysis plan or sample-size justification. The listed secondary outcomes have no numerical results in the record, limiting assessment of the study's stated pharmacokinetic-pharmacodynamic and response-related aims. The serious-event terms are described as top terms, but the record does not establish that the list is exhaustive or explain the denominator for their percentages.

These limitations mean that the reported results are best understood as a descriptive safety account for this pilot. They do not support broad claims about causality, comparative safety, antileukemic response, or generalizability to populations and treatment settings not described in the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: NOPHO ALL-2008 Pilot Study on Consolidation Therapy for Children and Adolescents With Acute Lymphoblastic Leukemia — NCT00548431.
• Registry record last updated 2017-01-09; status last verified 2016-11.
• Results first posted 2010-11-03.
• 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

NCT00548431 is a completed Phase II, single-group pilot study sponsored by Copenhagen University Hospital, Rigshospitalet. The registry lists a start date of 2007-12 and primary completion in 2009-01. It concerns individualized 6-mercaptopurine dose increments in children and young adults with acute lymphoblastic leukemia receiving high-dose methotrexate and PEG-asparaginase.

The primary outcome counts participants with serious adverse events or adverse events over 3 months (79 days). The posted results report 26 participants with serious adverse events and 23 with other adverse events, with 38 at risk for each. Neutropenic fever, Hypoglycemia, pancreatitis, and PRES are listed among the top serious-event terms. The registry also lists secondary outcomes for 6-thioguanine nucleotide incorporation and asparaginase antibody production, but their numerical results are not reported in the registry record.

With no control group, the results are descriptive rather than comparative. The registry does not report a statistical analysis plan, confidence intervals, or details on missing data and analysis populations.