Phase II Study of Combined Chemotherapy With Arsenic Trioxide in Stage 4/M Neuroblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Study of Combined Chemotherapy With Arsenic Trioxide in Stage 4/M Neuroblastoma (NCT03503864), a na phase 2 study. The primary outcome is Objective Response Rate.

2. Clinical Question

The study is intended to explore and evaluate the efficacy and safety of combined chemotherapy with arsenic trioxide in stage 4/M neuroblastoma. With a single-group design, the primary question is whether participants treated with the combination meet the specified response definition, not whether outcomes differ from those under a concurrent alternative. Any observed response would need to be interpreted in that context: the design can describe outcomes among treated participants, but by itself cannot isolate the effect of arsenic trioxide from the combined regimen or from other influences on response.

The registry also lists overall survival rate, progression-free survival rate, and participants with adverse events as secondary outcomes. Their definitions, timeframes, and results are not reported in the registry record. The primary response timeframe is specified as four weeks after induction chemotherapy, while longer-term outcome details are not available in the record.

3. Trial Design

This is a Phase II, prospective, single-arm, open-label, multi-center study of combined chemotherapy with arsenic trioxide in stage 4/M neuroblastoma. The registry lists planned enrollment of 80. Allocation is not applicable, masking is none, and the model is single group. Participants in the described arm receive combined induction chemotherapy with arsenic trioxide.

The registry record lists a start date of 2017-06-12, a primary completion date of 2023-08-30, and a status of active, not recruiting. These entries describe the record's stated timeline and status; they do not establish whether the primary endpoint has been analyzed. The registry lists four outcome measures and zero analyses. Primary outcome results are not reported in the registry record.

Because the study has one treatment group, the posted design does not include a randomized or concurrent control comparison. This matters for interpretation: the study can report outcomes in the enrolled group, but a response rate alone cannot establish how outcomes would have differed under another treatment or under no arsenic trioxide. Open-label status means masking is listed as none; the registry does not report further details on outcome assessment procedures or safeguards against assessment bias.

The endpoint description says response is evaluated four weeks after ATO-combined induction chemotherapy. It defines complete remission as disappearance of all lesions maintained for at least 4 weeks, and partial remission as estimated tumor size reduction by more than 50%, maintained for at least 4 weeks. The description refers to Response Evaluation Criteria In Solid Tumors Criteria and WHO criteria, and says target lesions are assessed by MRI or CT. Further protocol details, including eligibility criteria, treatment schedules, follow-up procedures, and the statistical analysis plan, are not reported in the registry record.

The study is listed as active, not recruiting, rather than as completed. The posted status should therefore be read separately from whether results are available: the record contains selected safety counts, but no primary response analysis. The reason the planned enrollment and safety-group denominator differ is not reported in the registry record.

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.

Before assignment: 6 patients changed therapeutic regimen，7 patient withdrew consent.

Overall Study

Reasons for not completing this period:

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 Objective Response Rate, measured over Four weeks after ATO-combined induction chemotherapy.

The primary endpoint is objective response rate, expressed in the registry description as the percentage of patients with complete remission or partial remission after induction chemotherapy combined with arsenic trioxide. The assessment timeframe is four weeks after ATO-combined induction chemotherapy. The registry specifies that complete remission means all lesions completely disappear and remain absent for at least 4 weeks. Partial remission means estimated tumor size reduction by more than 50%, maintained for at least 4 weeks. Target lesions are assessed by MRI or CT under the criteria named in the record.

Response endpoints are used to summarize tumor response according to a stated assessment rule at a specified time. A consistent rule makes the outcome interpretable as a count of participants meeting the response definition, relative to the group assessed. General statistical context: a response rate is a binary-outcome summary, because each participant is categorized as meeting or not meeting the response definition for the analysis. It does not, on its own, describe the duration of response or survival.

The registry record does not report the number of participants who achieved complete or partial remission, the response rate, or an uncertainty interval. It also does not report the analysis denominator or how missing response assessments were handled. Consequently, the primary endpoint is defined, but its observed result and precision cannot be evaluated from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a binary primary endpoint: a participant either meets the stated complete or partial remission definition or does not. The endpoint is named objective response rate, and its assessment is scheduled four weeks after ATO-combined induction chemotherapy. However, no primary endpoint result or analysis is reported in the registry record. The following statistical explanations are general and do not describe an analysis plan confirmed for this study.

How a response rate is estimated

General: a response rate is estimated by dividing the number of participants meeting the response definition by the number included in the endpoint analysis. The denominator is important: it might be all enrolled participants, all treated participants, or only those with an evaluable assessment, depending on the prespecified analysis approach. The registry record does not report which population or denominator was used for this endpoint, nor does it report a response count. No rate can therefore be reconstructed from the posted information.

General: uncertainty around a binary-outcome estimate can be described with a confidence interval. The interval expresses how compatible a range of underlying response probabilities is with the observed data under the interval method's assumptions. Its width depends in part on the number of observations and the observed response frequency. Since the response count and analysis denominator are not reported, neither an interval nor the precision of the primary estimate can be evaluated.

What a single-group design can establish

General: a single-group study can estimate the frequency of an outcome among participants who receive the study regimen, provided the outcome and analysis population are defined and results are reported. It does not directly estimate the difference in outcomes between the regimen and a concurrent alternative. Without a control group, changes or outcomes may also reflect participant selection, disease course, other care, or the way outcomes are assessed. The record lists no allocation to a control arm and no masking.

General: a p-value tests compatibility between observed data and a specified statistical model or null hypothesis; it is not a measure of effect size or clinical importance. The registry record reports zero analyses and no p-value for the primary endpoint. It does not report the hypothesis, statistical test, model, or decision threshold intended for the endpoint. Those details should not be inferred from the Phase II designation or from the endpoint name.

Assessment rules and measurement

The endpoint description sets out criteria for complete and partial remission and names MRI or CT as assessment methods for target lesions. General: outcome criteria are intended to make classification more consistent, but interpretation can still depend on what was assessed, when it was assessed, and how missing or uncertain findings were handled. The registry record does not report assessor training, independent review, adjudication, or details of how discrepancies between imaging assessments would be resolved.

The registry's wording refers to Response Evaluation Criteria In Solid Tumors Criteria and WHO criteria. It does not report additional operational details that would clarify how the stated criteria were implemented in analysis. The record also does not report whether response was analyzed as one combined category, whether complete and partial responses were separately tabulated, or whether any sensitivity analyses were planned.

Planning assumptions and observed evidence

The record includes general sample-size planning assumptions: a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as stated fractions of an observed effect. It notes that time-to-event planning uses total events and other planning figures use participants per arm. These are described as planning illustrations computed from an observed effect, not as the trial's own design. They do not establish the rationale for the registered enrollment of 80, and they are not observed power or study results. No specific planning values are reported in the record.

There is an important design distinction: the registered study is single group, whereas the planning illustration describes equal allocation between two arms. The planning assumptions therefore should not be read as proof that this study had two randomized arms. The record does not report a sample-size justification specific to this single-group study.

Safety counts and statistical context

The posted safety group lists participants at risk and affected participants for serious and other adverse events. General: an event count is more interpretable when its definition, observation period, analysis population, and handling of repeated events are clear. A count of participants with at least one event is different from a count of all event occurrences. The registry labels the measure as participants affected, but does not provide event-level counts, observation time, or details of repeated events. The safety entries are therefore descriptive and limited to the reported group counts.

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("ATO-combined Chemotherapy")
n      <- c(67)
events <- c(62)
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  ATO-combined Chemotherapy  67  62  92.5  83.4  97.5  83.7  96.8  83.7  96.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and secondary outcomes, but it does not report a statistical analysis plan, a hierarchy of hypotheses, or a multiplicity adjustment. It also lists four outcome measures and zero analyses. The record does not say whether all listed outcomes were intended for formal hypothesis testing, whether some were descriptive, or how interpretation would account for examining more than one outcome. Those details are not reported in the registry record.

General statistical context: when multiple outcomes or multiple analyses are tested, the chance of at least one apparently unusual result can increase if each is interpreted independently. Prespecified outcome priorities and an appropriate multiplicity strategy can help distinguish confirmatory questions from exploratory ones. No strategy can be attributed to this study from the available record.

The registry defines the primary response timeframe but does not report an endpoint analysis population, a missing-data rule, or the number of participants with missing or unevaluable assessments. It is therefore unknown whether participants without an assessment would be excluded, counted as nonresponders, or handled in another way. General: different missing-data approaches can lead to different estimates, especially when the probability of missingness is related to outcome or participant characteristics.

The record does not report whether analyses were planned for all enrolled participants, treated participants, or another population. It also does not report an interim analysis plan, a stopping rule, or procedures for censoring or follow-up in the listed survival outcomes. These absences limit assessment of how analyses would preserve the registered question and how attrition or incomplete follow-up might affect estimates.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists one safety group, titled ATO-combined Chemotherapy. For serious adverse events, 67 participants are listed as at risk and 0 as affected. For other adverse events, 67 are listed as at risk and 67 as affected. The record separately lists 22 deaths. These are descriptive counts as posted; the record does not give event terms for serious adverse events or details of the other events.

The safety entries do not specify the observation period, the number of event occurrences, severity grades, timing, or whether participants could be counted in more than one event category. The record does not explain how the deaths relate to the adverse-event categories, nor does it provide their timing or causes. It also does not explain why the safety denominator of 67 differs from planned enrollment of 80.

General statistical context: a count of affected participants does not convey how long participants were followed or how many events each participant experienced. A zero count in the posted serious-event field is a statement about that registry entry; without further information, it cannot establish that no serious event occurred outside the recorded population or observation period. The safety information is therefore limited to the listed counts and should not be treated as a complete safety analysis.

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

The registry record establishes that the study is a prospective, open-label, multi-center, single-group Phase II study of combined induction chemotherapy with arsenic trioxide in stage 4/M neuroblastoma. It specifies objective response rate as the primary endpoint and gives its assessment timeframe and response definitions. It also reports selected safety counts for the ATO-combined Chemotherapy group.

Those details do not amount to a posted efficacy result. The record does not report how many participants met the primary response definition, the response rate, or an estimate of uncertainty. It is not possible to say from the posted primary outcome information how often response occurred or how precisely it was measured. The registered study status does not substitute for an outcome analysis.

The design also does not provide a concurrent control group. General: an outcome observed in a treated group is not the same as an estimate of the treatment's effect relative to another option. Without a control arm, the result cannot separate the contribution of arsenic trioxide from the chemotherapy combination or other influences. No comparison with an external group is reported in the registry record.

The safety counts show 0 participants affected by serious adverse events among 67 at risk and 67 affected by other adverse events among 67 at risk, with 22 deaths separately listed. They do not describe event timing, severity details, follow-up duration, causes of death, or event terms. The numbers should not be expanded into claims about the complete safety experience.

The record lists secondary outcomes for overall survival, progression-free survival, and adverse events, but does not report their results or detailed analysis definitions. It also does not report missing-data procedures, analysis populations, or multiplicity handling. Accordingly, the available record supports a description of the registered design and certain counts, but does not support a full evaluation of efficacy or safety, or a comparative conclusion.

14. Why This Trial Matters Statistically

This study raises statistical questions that are important to interpreting early-phase clinical research: what outcome is being measured, how the response is defined, which participants contribute to the estimate, and what conclusions a single-group design can support. The registry gives a response definition and an assessment timeframe, which helps make the intended endpoint recognizable. But it does not report the observed response result or the analysis denominator, so the central endpoint cannot be evaluated from the record.

The single-group design is especially important. A response rate in treated participants can describe their observed outcomes, but it does not offer a direct comparison with a concurrent control group. This limits causal interpretation and means that a treatment effect relative to another regimen is not estimated by the registered design. The distinction between an outcome description and a comparative effect is fundamental to reading the study accurately.

The record also illustrates why denominators and observation periods matter for safety interpretation. It lists 67 participants at risk for adverse-event measures, 0 affected by serious adverse events, 67 affected by other adverse events, and 22 deaths. Without definitions and follow-up details, these counts cannot convey the full event experience or support comparisons across studies.

Finally, the record includes planning assumptions that describe an illustration rather than the study's own design. Separating planning calculations from observed evidence prevents a sample-size exercise from being mistaken for results or for a prospective justification. In this case, the registry reports no analyses, and the primary outcome findings are not reported. Statistical interpretation therefore depends as much on recognizing what is absent as on describing the entries that are present.

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 is that the registry record does not report the primary response count, rate, uncertainty interval, or analysis denominator. The endpoint definition is available, but there is no posted primary result to interpret. The record also lists zero analyses, so no primary inferential analysis is reported.

The study has a single-group, open-label design with no concurrent comparator. This restricts interpretation to the treated group and prevents a direct randomized comparison. The registry does not report details of response assessment oversight, such as independent review or adjudication. It also does not give enough operational information to evaluate how the named response criteria were applied in practice.

Planned enrollment is 80, while the safety group lists 67 at risk. The reason for this difference is not reported in the registry record. Nor does the record report the number with primary endpoint assessments, the analysis population, exclusions, withdrawals, or missing-data handling. This prevents assessment of whether the reported safety group represents the population intended for the primary analysis.

Safety information is limited to participant counts and a separate death count. Event terms, severity details beyond the serious-event grouping, timing, duration of observation, causes of death, and repeated-event handling are not reported. The secondary outcome names are listed, but their definitions, timeframes, and results are not reported in the registry record.

The record does not report the protocol-level statistical plan, sample-size justification for the single-group design, interim analyses, multiplicity procedures, or analysis populations. These limitations leave uncertainty about how outcomes were intended to be analyzed and how incomplete follow-up or multiple outcomes would be addressed. The posted record should therefore be interpreted as a limited account of design and selected safety data, not as a full report of trial findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase II Study of Combined Chemotherapy With Arsenic Trioxide in Stage 4/M Neuroblastoma — NCT03503864.
• Registry record last updated 2025-05-21; status last verified 2025-05.
• Results first posted 2025-05-21.
• 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 describes NCT03503864, a Phase II, prospective, open-label, multi-center, single-group study of combined chemotherapy with arsenic trioxide in stage 4/M neuroblastoma. Planned enrollment is 80. The listed status is active, not recruiting; the start date is 2017-06-12 and the primary completion date is 2023-08-30.

The primary endpoint is objective response rate four weeks after ATO-combined induction chemotherapy, with response defined using the criteria stated in the registry. The record lists overall survival rate, progression-free survival rate, and participants with adverse events as secondary outcomes. It lists four outcome measures and zero analyses; primary response results are not reported in the registry record.

The safety group lists 67 participants at risk for serious and other adverse events, 0 affected by serious adverse events, 67 affected by other adverse events, and 22 deaths. Further event details and the reason for the difference between planned enrollment and the safety denominator are not reported in the registry record.