Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia (NCT01523782), a non-randomized phase 2 study. The primary outcome is Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment.

2. Clinical Question

The clinical question combines dose selection with an early biological response measure. The endpoint is not described as a comparison of GRASPA against no GRASPA or against another treatment. Instead, it asks whether patients in the dose groups met a defined plasma asparagine depletion criterion, while the broader study purpose also includes tolerability. The record calls the main evaluation criterion a composite efficacy/toxicity criterion, but does not give enough detail to reconstruct its components or decision rule.

Because allocation was non-randomized, observed outcomes across dose groups would not by themselves establish that dose caused any differences. The groups may differ for reasons not described in the registry record, and the number of participants in each group is small. The registry record also does not report the primary endpoint results, so the extent to which patients met the response definition cannot be assessed from this record.

3. Trial Design

This is a phase 2 study, described in its official title as an escalating dose phase IIa study. It enrolled 30 participants and is listed as completed. The recorded study start is 2009-04 and primary completion is 2011-01. ERYtech Pharma is identified as the sponsor. The condition is acute lymphoblastic leukemia.

The design is non-randomized, unmasked, and parallel. Three GRASPA dose groups are described: 50 IU/kg, 100 IU/kg, and 150 IU/kg. Each group received GRASPA on day 3 of Induction 1. For the 50 IU/kg and 100 IU/kg groups, the arm descriptions say that a second injection at the identical dose would be given on Day 6 of Induction 2 if no toxicity related to the investigational product was observed and the patient's health allowed it. The 150 IU/kg description specifies a second identical-dose injection on Day 6 of Induction 2 but does not include the same conditional wording. Further operational details are not reported in the registry record.

All groups received GRASPA with polychemotherapy during induction; the chemotherapy regimen is not described in the record. Since participants were not randomly allocated, the dose groups should not be read as randomized treatment arms. The record does not state how participants entered each dose group, whether enrollment proceeded strictly from lower to higher doses, or what rules governed dose escalation and dose selection.

Masking is listed as none. The registry record does not report whether outcome assessment was standardized or independently reviewed. It also does not provide a sample-size justification, the intended size of each dose group, or details of the analysis population. The overall enrollment is reported, but the adverse-event group counts are not a substitute for a participant flow account or endpoint-specific denominators.

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 Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment, measured over 7 days after the first administration of GRASPA® during Induction 1.

The primary endpoint is titled “Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment.” It is a participant-level response measure. A patient is described as responding if plasma asparagine (Asn) concentration is at or below 2µM, indicating depletion, for a duration of at least 7 days after GRASPA administration during Induction 1. The timeframe is 7 days after the first administration of GRASPA during Induction 1.

This endpoint is used as an early biological measure of whether the treatment regimen achieves the specified reduction in plasma asparagine. It is not, by itself, a measure of longer-term clinical outcome. The registry record does not report a response count, response percentage, estimate of uncertainty, or the number of participants assessed for this endpoint. It also does not explain how missing concentration measurements, measurements near the threshold, or incomplete follow-up were handled.

The record describes the main evaluation criterion as a composite efficacy/toxicity criterion, while the named primary endpoint focuses on the efficacy response definition. The exact way toxicity and efficacy were combined, if they were combined into a formal decision rule, is not reported in the registry record. Therefore the response definition can be described, but the full dose-selection criterion cannot be reconstructed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant-level response endpoint mean?

The primary outcome is expressed as a percentage of patients meeting a specified response definition. The definition is based on a measured plasma asparagine concentration and a duration: concentration at or below 2µM for at least 7 days after administration during Induction 1. Conceptually, an endpoint of this kind classifies each assessed patient as meeting or not meeting the criterion, then describes the proportion who meet it. That proportion depends on both the response count and the number assessed. Neither is reported in the registry record for this endpoint.

Reducing a continuous laboratory measurement to a threshold-based response can make a criterion easier to interpret, but it also discards information about how far measurements lie above or below the threshold. General statistical point: observations close to a cutoff can be classified differently because of ordinary measurement variation, while the endpoint treats all qualifying values alike. The registry record does not describe measurement schedules, laboratory methods, or rules for handling values around the threshold.

Why does the non-randomized design matter?

Random allocation is one way to make treatment groups comparable on average with respect to measured and unmeasured characteristics. Here, allocation is explicitly listed as non-randomized. The dose groups therefore should not be interpreted as if they were randomized arms. General statistical point: when treatment assignment is related to patient characteristics, those characteristics can also be related to outcomes, making a difference between groups difficult to attribute to dose.

The record does not explain how participants were assigned to the dose groups, whether selection depended on earlier tolerance, or which factors influenced assignment. It also does not report a prespecified adjusted analysis. Without those details, the degree of comparability between groups cannot be evaluated. The three dose levels describe the treatment structure, not proof of a controlled dose-response comparison.

What can be learned from a confidence interval?

General statistical explanation: a confidence interval gives a range of values compatible with the data under a specified statistical model and method. It conveys the uncertainty around an estimate, rather than only presenting a single point estimate. A narrower interval indicates greater precision under that method; a wider interval indicates greater uncertainty. A confidence interval is not a guarantee that the true value lies inside its particular limits.

No primary response estimate or confidence interval is reported in the registry record. Thus, the precision of the response percentage cannot be evaluated. The total enrollment alone does not reveal the number assessed for the endpoint, the number with a qualifying response, or the amount of uncertainty around a result.

What does over-dispersion mean?

General statistical explanation: for count data, over-dispersion occurs when the variability is greater than expected under a simple model such as a Poisson model. If that extra variability is ignored, standard errors may be too small and confidence intervals may be too narrow. The registry record does not report a count-model analysis or dispersion estimate for the primary endpoint, which is a participant response measure rather than a reported count rate. No claim about over-dispersion in this study can be made from the record.

How should planning calculations be read?

General statistical explanation: sample-size planning estimates describe a hypothetical future study under stated assumptions. They are not observed outcomes and do not show the probability that a completed study detected an effect. The registry record's stated planning assumptions refer to a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. For time-to-event calculations, the stated convention is a total number of events; other planning calculations are expressed as participants per arm.

These assumptions are planning conventions, not evidence about how this non-randomized dose-escalation study was designed. The registry record does not report its own sample-size justification or a statistical analysis plan. The record also does not report the observed primary effect needed to interpret an illustration based on that effect. Any sample-size illustration should therefore be understood as a planning exercise, not observed power, and not as a finding about the trial's efficacy.

Why does the analysis record matter?

The record lists 14 outcome measures but no analyses. This absence means the registered material does not give the estimates, uncertainty intervals, or tests required to evaluate the outcomes statistically. General statistical point: a planned endpoint definition and a completed analysis answer different questions. The endpoint states what investigators intended to measure; the analysis reports what was observed and how uncertainty was quantified. Here, the primary response definition is available, but the corresponding results are not reported in the registry 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("GRASPA 50 IU/kg", "GRASPA 100 IU/kg", "GRASPA 150 IU/kg")
n      <- c(3, 13, 14)
events <- c(0, 11, 10)
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  GRASPA 50 IU/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  GRASPA 100 IU/kg  13  11  84.6  54.6  98.1  57.8  95.7  57.2  95.3
ARM  GRASPA 150 IU/kg  14  10  71.4  41.9  91.6  45.4  88.3  44.9  88.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 14 outcome measures and identifies several secondary biomarker outcomes: plasma concentrations of asparagine, aspartic acid, glutamine, and glutamic acid, and cerebrospinal fluid concentrations of those same analytes. It lists no analyses. It therefore does not report which outcomes were analyzed, how many comparisons were made, or whether any adjustment for multiple testing was used.

General statistical explanation: when many outcomes or comparisons are examined, the chance of obtaining at least one apparently notable result by chance can increase. Multiplicity procedures can manage that issue, but the suitable approach depends on the prespecified questions and analysis plan. Such a plan is not reported in the registry record. No claim can be made about whether multiplicity was addressed in the study analyses.

Missing-data methods and analysis populations are also not reported in the registry record. There is no description of how missing laboratory measurements, withdrawal, incomplete follow-up, or unevaluable responses were handled. The record does not state whether the primary endpoint was analyzed among all enrolled participants, only those who received treatment, or another defined group. The recorded enrollment and the adverse-event risk sets do not establish the endpoint-specific denominator.

These omissions limit reproducibility and interpretation. Without analysis populations, missing-data rules, and multiplicity information, a reader cannot determine how the listed outcomes were converted into estimates or how the analysis accounted for incomplete data and multiple questions.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: leukemia recurrent (46.2%), escherichia sepsis (33.3%), febrile bone marrow aplasia (33.3%), arrythmia (33.3%), bacterial sepsis (33.3%).

The registry record lists serious and other adverse-event counts by GRASPA dose group, with participants at risk and affected, plus deaths. For GRASPA 50 IU/kg, the serious-event counts are 3 at risk and 3 affected; the other-event counts are 3 at risk and 3 affected, with 1 death. For GRASPA 100 IU/kg, the corresponding counts are 13 and 13 for serious events, 13 and 13 for other events, and 2 deaths. For GRASPA 150 IU/kg, the serious-event counts are 14 at risk and 13 affected; the other-event counts are 14 and 14, with 3 deaths.

The record lists serious-event terms including Leukemia recurrent (46.2%), Escherichia sepsis (33.3%), Febrile bone marrow aplasia (33.3%), Arrythmia (33.3%), Bacterial Sepsis (33.3%), and Diverticulitis (33.3%). The denominator and the rules used to count these terms are not reported in the registry record. These percentages should therefore be read as entries in the record, not as directly comparable event risks across dose groups.

These counts do not establish that GRASPA caused an event or death. The record does not provide attribution, timing, exposure-adjusted rates, or a comparison with a control group. Since allocation was non-randomized, dose-group safety counts are descriptive rather than a like-for-like treatment comparison.

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

The record documents a phase 2 dose-escalation study of GRASPA with polychemotherapy in patients aged 55 years and over with Philadelphia chromosome-negative ALL. Its primary efficacy question is clearly framed around plasma asparagine depletion: whether concentration was at or below 2µM for at least 7 days after GRASPA administration during Induction 1. The intended broader purpose was to identify a maximum tolerated and efficient dose.

However, the primary endpoint result is not reported in the registry record. There is no response count, percentage, uncertainty estimate, or analysis to support a conclusion about how often the specified biological response occurred. The record likewise does not state which dose was selected or show a formal efficacy-toxicity decision. The absence of those results is not evidence that the endpoint was or was not met.

The safety entries provide descriptive counts for the three dose groups and list several serious-event terms. They do not establish causation. No randomized control group is described, and the record does not provide details needed to compare safety rates fairly, such as event attribution, timing, or exposure-adjusted measures. The death counts are reported by dose group, but the record does not offer an analysis of their relationship to study treatment.

The design and posted information also do not establish that differences across dose levels were caused by dose. Allocation was non-randomized, and the assignment process is not reported. Even with complete outcome results, those features would require cautious interpretation. The listed groups are dose cohorts, not randomized comparison arms.

In statistical terms, this record supports a description of the study question, design, endpoint definition, and selected safety entries. It does not support a conclusion about treatment efficacy, comparative safety, or the optimal dose. Those are not negative findings; they are matters that remain unreported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable because dose selection is not the same question as a conventional randomized treatment comparison. A dose-escalation study seeks information about how a candidate dose behaves in the context of a regimen, including tolerability and a biological response. The record describes three GRASPA dose groups and states that the study aimed to determine a maximum tolerated and efficient dose. It also describes a response threshold based on plasma asparagine depletion.

Those aims require clear rules. A reader would need to know how dose escalation proceeded, what counted as an unacceptable toxicity, how efficacy and toxicity were combined, and how dose selection was made. The registry record does not report those details. The absence makes it difficult to judge whether the observed design, if results were available, would answer the intended dose-selection question.

The non-randomized allocation is also important. Dose groups in an escalating-dose context may not be interchangeable populations. Statistical descriptions should distinguish observed group patterns from causal conclusions about dose. The record does not report an adjustment strategy or enough information to assess group comparability.

Finally, registration of an endpoint is not a substitute for reporting its analysis. The primary endpoint is defined, but its observed response count and percentage are not reported. The record lists 14 outcome measures and no analyses. This distinction matters to evidence appraisal: precise endpoint definitions help clarify the intended question, while results and uncertainty estimates are needed to evaluate what the study found. Here, the question is identifiable, but the posted record leaves the answer unreported.

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.

Several trial-specific limitations constrain interpretation of the registry record. The design is non-randomized and unmasked, and no randomized control group is described. The method used to assign patients to dose groups is not reported, so potential differences between groups cannot be assessed. The record also does not explain the dose-escalation procedure or the rules used to select a dose.

The central efficacy result is absent: response counts, percentages, endpoint-specific denominators, and estimates of uncertainty are not reported in the registry record. Although the main evaluation criterion is described as a composite efficacy/toxicity criterion, the components and decision rule are not reported. The analysis population, missing-data handling, and statistical analysis plan are also not reported.

The record lists secondary biomarker outcomes and 14 outcome measures overall, but no analyses. It does not report whether multiplicity was addressed. Safety entries provide event counts and selected serious-event terms, but the record does not specify event attribution, timing, exposure-adjusted measures, or the denominators for the listed serious-event percentages. These details are needed to make stronger comparisons or assess causal relationships.

The chemotherapy regimen and further eligibility details are not reported in the registry record. The record also does not describe the measurement schedule or laboratory procedures for the primary endpoint. These omissions limit the ability to evaluate reproducibility, endpoint assessment, and the relevance of the dose-group observations beyond the registered descriptions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia — NCT01523782.
• Registry record last updated 2021-10-15; status last verified 2018-06.
• Results first posted 2018-06-14.
• 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

NCT01523782 is a completed phase 2, non-randomized, unmasked, parallel study sponsored by ERYtech Pharma. It enrolled 30 participants with acute lymphoblastic leukemia and examined GRASPA with polychemotherapy in patients aged 55 years and over with Philadelphia chromosome-negative ALL. The recorded start is 2009-04 and primary completion is 2011-01.

The study described dose groups of GRASPA 50 IU/kg, 100 IU/kg, and 150 IU/kg. Its primary efficacy endpoint was the percentage of patients with plasma asparagine at or below 2µM for at least 7 days after administration during Induction 1. The stated study purpose was to determine a maximum tolerated and efficient dose.

The registry record does not report primary endpoint results or analyses. It lists adverse-event counts by dose group and several serious-event terms, but does not provide enough context for causal or comparative interpretation. The allocation process, analysis populations, missing-data methods, multiplicity procedures, and statistical analysis plan are not reported in the registry record.