High Dose Ascorbate With Preoperative Radiation in Patients With Locally Advanced Soft Tissue Sarcomas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for High Dose Ascorbate With Preoperative Radiation in Patients With Locally Advanced Soft Tissue Sarcomas (NCT03508726), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Pathologic Tumor Necrosis ≥ 95% Following Concurrent Radiation Therapy and Ascorbate.

2. Clinical Question

3. Trial Design

This completed study is registered as a phase 1b/2, single-group, nonrandomized, open-label clinical trial. The registry records enrollment of 25. Its official title describes neoadjuvant high-dose ascorbate given concurrently with preoperative radiation for locally advanced soft tissue sarcomas of the extremity, trunk and retroperitoneum. The brief summary describes the study as assessing the efficacy of concurrent high-dose ascorbate with radiotherapy in people with locally advanced, resectable, high-grade sarcomas.

The study included a Phase I dose escalation cohort and a Phase II cohort. The registry reports 6 participants enrolled to the Phase I portion and assessed for the primary pathology endpoint, and 19 enrolled to Phase II and assessed for that endpoint. The intervention descriptions state that participants received radiation over 5 weeks and ascorbate infusions three times a week until radiation ended. Surgery was described as occurring 4-6 weeks after the end of radiation. The primary endpoint population description states that participants in both phase cohorts received a 75 mg IV dose three times a week.

There was no random allocation, masking or separate control group recorded. The phase cohorts should therefore not be read as randomized comparison arms. The registry dates the study start to 2019-06-27 and primary completion to 2022-06-03, and lists the overall status as completed. These design details identify the treatment context and timing, but do not by themselves give the primary endpoint result.

The registry lists secondary outcomes including event-free survival at 2 years, overall response rate, overall survival at 2 years, skin toxicity, labile iron and diffusion-weighted imaging sequences. Their results are not reported in the registry record. The statistical analysis plan, including any planned comparisons or adjustment methods, is also 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 6 participants enrolled in the Phase 1 dose escalation portion of the trial and were assessed for dose limiting toxicities. All participants received 75 mg Ascorbate IV dose three times a week.

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 Pathologic Tumor Necrosis ≥ 95% Following Concurrent Radiation Therapy and Ascorbate, measured over Start of treatment up to 6 weeks after the last ascorbate infusion.

The primary endpoint is a count: the number of participants with pathologic tumor necrosis of at least 95% following concurrent radiation therapy and ascorbate. The assessment window is from the start of treatment through 6 weeks after the last ascorbate infusion. The registry describes the endpoint as an estimate of pathological complete response rates in people with locally advanced, high-grade soft tissue sarcomas.

Pathology after preoperative treatment can describe the extent of tumor necrosis in tissue examined after treatment. A threshold-based endpoint turns that finding into a classification: participants either meet the stated necrosis threshold or do not. The count can be used to describe how often the defined pathology finding occurred in the assessed cohort. Interpreting it as a treatment effect would require an appropriate comparison and a reported result; this study has no randomized control group in the registry record.

The posted record gives the endpoint definition and says that participants in both phase cohorts were assessed, but it does not report the number meeting the threshold. It also does not report an endpoint estimate, confidence interval or test result. The endpoint's intended use is therefore clear, while its observed result and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a count of participants meeting a binary pathology definition: pathologic tumor necrosis of at least 95%. In general, a binary endpoint classifies each assessed participant into one of two categories, such as meeting or not meeting a defined threshold. A count reports the number meeting the criterion; a proportion expresses that count relative to the participants assessed. The record reports the assessed cohort sizes but does not report the count meeting the criterion, so neither the primary count nor its proportion is available for interpretation.

What does a count show?

A count is a direct description of how many participants had the defined event, but it does not alone communicate how precisely the underlying event frequency is estimated. General statistical practice may pair a count or proportion with a confidence interval. A confidence interval describes a range of values compatible with the observed data under a particular statistical method and its assumptions. Wider intervals generally indicate less precision; narrower intervals indicate greater precision. No primary endpoint interval is reported in the registry record, and the missing endpoint count prevents a recalculation from the posted information.

The endpoint is assessed in participants treated with ascorbate alongside radiation, and the study is recorded as a single group with no randomization or masking. In general, a single-group outcome frequency is descriptive of that observed cohort. It does not supply the counterfactual outcome that might have occurred for comparable participants under another treatment. Random allocation can help balance measured and unmeasured factors between treatment groups, on average, but this trial did not use random allocation according to the registry. No causal comparison with radiation alone is reported.

Why are the phase cohorts not a control comparison?

The record distinguishes a Phase I dose escalation cohort and a Phase II cohort, but describes both as receiving 75 mg IV ascorbate three times a week for the primary endpoint population. They are portions of a single study, not assigned treatment and control groups. In general, comparing outcomes across cohorts enrolled in different phases can mix treatment effects with differences in study stage, participant selection, timing or other factors. The registry does not report a randomized comparison between the cohorts or an adjusted analysis designed to address such differences.

The primary endpoint has a specified assessment window: from treatment start through 6 weeks after the last ascorbate infusion. Clear timing matters because a binary outcome depends on when and how it is assessed. The registry describes pathology assessment but does not report additional details about pathology review, reviewer masking, adjudication or rules for participants whose pathology could not be assessed. Those details are not reported in the registry record.

What can the analysis entries establish?

The record lists no analysis entries. It does not report an analysis population definition beyond noting participants assessed for the primary endpoint in each phase cohort. It does not report a statistical model, confidence interval method, hypothesis test, adjustment procedure or handling of missing endpoint assessments. These elements affect how an estimate is calculated and interpreted. Their absence means the analysis cannot be reconstructed from the registry description, and no method should be presumed.

The record lists secondary outcomes, including event-free survival at 2 years and overall survival at 2 years. Time-to-event outcomes generally involve follow-up time and event status, and their interpretation can depend on censoring, follow-up completeness and the analysis method. The registry does not report results or analysis details for those outcomes. The same caution applies to the other listed secondary outcomes: the titles establish what was planned for assessment, not what was observed.

How should planning illustrations be read?

General sample-size calculations describe how much information a proposed study might need under specified assumptions. The registry's planning material is characterized as an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation; it describes the effect to detect as a stated fraction of the observed effect. These are planning assumptions, not a report of the trial's original design rationale. The registry does not report the original sample-size justification.

Those illustrations are not observed power. Observed power is not a substitute for reading the estimate and its uncertainty, and a planning calculation does not show whether the primary endpoint was met. Moreover, the listed illustration assumptions include equal allocation between two arms, whereas the registered trial is single-group and has no randomized control arm. Such assumptions should not be mistaken for the trial's design or for a comparative result. The illustration's numerical outputs are not because the primary endpoint result and corresponding effect are not reported in the registry record.

Over-dispersion is a general issue for count data when variability exceeds what a simple model assumes. It matters when selecting and assessing a count model, because a model that understates variability can produce uncertainty estimates that are too narrow. The primary endpoint is a participant count defined by a binary threshold, not a reported recurrent-event count, and the record does not report a count model or dispersion estimate. No over-dispersion adjustment can therefore be attributed to this analysis.

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("Phase I: Ascorbate 75 mg IV Infusion", "Phase II: Ascorbate 75 mg IV Infusion")
n      <- c(6, 19)
events <- c(2, 1)
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  Phase I: Ascorbate 75 mg IV Infusion  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Phase II: Ascorbate 75 mg IV Infusion  19  1  5.3  0.1  26.0  0.9  24.6  1.2  24.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcome measures, including the primary pathology endpoint and secondary outcomes for event-free survival at 2 years, overall response rate, overall survival at 2 years, skin toxicity, labile iron and diffusion-weighted imaging sequences. It records 8 outcome measures, while the primary endpoint and secondary outcome titles do not provide results for those measures. The statistical analysis plan is not reported in the registry record.

When several outcomes are tested, the chance of at least one apparently notable result can increase if each is assessed without accounting for the number of tests. General approaches to multiplicity include prespecifying a primary outcome, adjusting inference across selected tests or treating secondary analyses as exploratory. The registry record does not report whether any such approach was planned or used, so no adjustment should be assumed.

The record does not report missing-data counts, reasons for missingness, imputation methods or sensitivity analyses. It notes that 6 Phase I participants and 19 Phase II participants were assessed for the primary pathology endpoint, but does not describe whether any enrolled participant lacked an assessment or how such cases would be handled. The analysis population beyond those stated assessment counts is not reported in the registry record.

These gaps affect both precision and interpretation. Missing outcome information can change an estimated frequency, while analysis-population choices determine which participants contribute to an estimate. Without the analysis details and outcome results, it is not possible to assess whether missingness or multiple testing influenced the reported findings.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (5.3%), jejunal obstruction (5.3%), fever (5.3%), bacteremia (5.3%), kidney infection (5.3%).

The registry reports serious adverse events separately for the Phase I and Phase II ascorbate cohorts. In Phase I, 0 of 6 participants were listed as affected by a serious adverse event; in Phase II, 4 of 19 were listed as affected. The record also lists other adverse events for 6 of 6 Phase I participants and 18 of 19 Phase II participants. Deaths are recorded as 0 in Phase I and 5 in Phase II. These are descriptive counts, not comparisons between randomized groups.

The listed serious-event terms are abdominal pain, jejunal obstruction, fever, bacteremia, kidney infection and dehydration, each recorded at 5.3%. The registry information does not clarify whether these terms refer to unique participants or overlapping events, nor does it provide enough detail to attribute an event to ascorbate, radiation, the underlying condition or another cause. The percentages should therefore be read as registry-reported figures, not recalculated or treated as causal estimates.

Because the study has no control arm, the counts cannot establish how event frequency compares with another treatment or with radiation alone. The registry does not report further details about event timing, severity grading, attribution or follow-up in the information. Safety counts describe what was recorded; they do not by themselves establish comparative safety.

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

The study addresses a clinically relevant statistical question: how often participants treated with preoperative radiation and concurrent ascorbate had at least 95% pathologic tumor necrosis. The registry defines that endpoint and its assessment window, and states that the Phase I and Phase II groups were assessed. However, the primary result itself is not reported in the registry record. The posted information therefore does not show how many participants met the pathology threshold or how precisely that frequency was estimated.

The design helps frame what any reported outcome could mean. This is a completed, open-label, nonrandomized, single-group study. Without a control group, an observed outcome frequency would describe participants who received the combined regimen, not isolate the effect of ascorbate from radiation or other influences. The cohorts should not be treated as randomized arms, even though the record reports separate Phase I and Phase II groups.

The registry does provide adverse-event counts, but their descriptive nature also matters. They do not establish comparative risk or identify the cause of events. The secondary outcomes are listed, but their results and statistical analyses are not reported in the registry record. For those outcomes, the registry identifies areas assessed or intended for assessment without showing the findings.

Accordingly, the appropriate conclusion from the posted record is limited: it documents the design, regimen, endpoint definition, assessment groups and selected safety counts, but it does not report the primary pathology outcome result. It does not establish whether the endpoint threshold was met at any particular frequency, how uncertain an estimate would be, or whether the combination differs from another treatment. No treatment recommendation follows from these registry entries.

14. Why This Trial Matters Statistically

This trial illustrates why design and outcome reporting must be read together. A clearly defined pathology threshold can make an endpoint interpretable, but the endpoint definition alone is not a finding. Without the number meeting the threshold and an estimate of its precision, readers cannot evaluate the primary result. The registry record is explicit about the intended pathology question while not reporting its outcome.

The study's single-group, nonrandomized structure is also central to statistical interpretation. A cohort outcome can be described, but the design does not provide a randomized contrast that separates the contribution of ascorbate from concurrent radiation or other factors. The Phase I and Phase II cohorts are part of the study rather than a treatment-versus-control comparison. Recognizing this distinction prevents descriptive data from being mistaken for evidence of a comparative effect.

Finally, the record shows the difference between a planning calculation and observed evidence. A sample-size illustration based on an observed effect is a planning aid, not observed power, and it does not fill in an unreported outcome. Statistical conclusions depend on the observed estimate, its uncertainty, the analysis population and the methods used. Several of those elements are not reported in the registry record. For biostatisticians and clinical researchers, the study is a useful reminder that registry entries can establish design and measurement details while leaving the central inferential result unavailable.

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 limitation for interpreting efficacy is that the registry record does not report the primary endpoint result. It states that participants in both phase cohorts were assessed for the pathology endpoint, but gives no number meeting the necrosis threshold, proportion, confidence interval or test result. The registry therefore does not support an estimate of the observed primary outcome from the information reported.

The single-group, nonrandomized design provides no randomized comparator. Even if an outcome estimate were available, it would describe the treated cohorts and would not isolate the contribution of ascorbate from concurrent radiation or other factors. The Phase I and Phase II cohorts should not be treated as equivalent to randomized arms. The open-label design and absence of reported details about pathology review further limit assessment of outcome measurement procedures.

The record does not report the statistical analysis plan, analysis population beyond the endpoint assessment counts, missing-data handling, multiplicity procedures or methods for the listed secondary outcomes. Secondary outcome results are also not reported in the registry record. Without these details, it is not possible to evaluate analysis choices, assess the handling of incomplete information or judge the precision of estimates.

The safety information is also limited to the posted descriptive counts and listed event terms. Further details about timing, attribution, severity grading and overlap among event categories are not reported in the registry record. These gaps preclude a comparative safety interpretation. The registry does provide the treatment schedule and endpoint window, but those protocol descriptions do not replace outcome estimates or the methods needed to interpret them.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: High Dose Ascorbate With Preoperative Radiation in Patients With Locally Advanced Soft Tissue Sarcomas — NCT03508726.
• Registry record last updated 2026-06-18; status last verified 2026-05.
• Results first posted 2023-06-06.
• 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, open-label, nonrandomized, single-group phase 1b/2 study of ascorbate given with preoperative radiation for locally advanced soft tissue sarcoma. It records enrollment of 25 and identifies Phase I and Phase II cohorts. The regimen description specifies radiation over 5 weeks and ascorbate infusions three times a week, with surgery 4-6 weeks after radiation ended. The primary endpoint counts participants with at least 95% pathologic tumor necrosis within the stated assessment window.

The record reports some adverse-event counts, but does not report the primary endpoint result, secondary outcome results, analysis plan, missing-data methods or multiplicity approach. With no randomized comparator, the study does not provide a like-for-like control comparison. The posted information establishes the design and intended measurement, but not the primary efficacy estimate or its precision.