This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Temozolomide and Ascorbic Acid in Treating Patients With Recurrent High-Grade Glioma (NCT02168270), a na phase 1 study. The primary outcome is Maximum Tolerated Dose of Ascorbic Acid in Combination With Temozolomide.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02168270 |
| Phase | Phase 1 |
| Condition | Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 4 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Nebraska |
| Results posted | Yes |
2. Clinical Question
Population
People with recurrent high-grade glioma were the intended population. The registry lists anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, glioblastoma, and gliosarcoma among the conditions. It does not report participant characteristics or how many participants had each condition.
Intervention
The study paired intravenous ascorbic acid with oral temozolomide. The treatment description specifies ascorbic acid administered over 90-120 minutes three times per week and temozolomide on days 1-28, with treatment repeating every 4 weeks for up to 12 courses unless disease progression or unacceptable toxicity occurred.
Comparator
There was no separate comparator group. The study is recorded as single-group, with allocation listed as NA and masking listed as none. It therefore does not provide a like-for-like comparison with temozolomide alone, another treatment, or a control group.
Primary question
The primary question was what maximum tolerated dose of ascorbic acid could be used in combination with temozolomide, using dose-limiting toxicity during 56 days to define tolerability. The registry defines the maximum tolerated dose as the highest dose tested with dose-limiting toxicity in no more than one of six evaluable patients. No participants were evaluable because the study was terminated after disease progression.
3. Trial Design
This was a phase I study of metronomic temozolomide and intravenous ascorbic acid for patients with recurrent high-grade glioma. The registry identifies the design as single-group, with allocation recorded as NA and no masking. Four participants enrolled. The sponsor was the University of Nebraska. The study started on 2014-06-16, had a primary completion date of 2015-08-20, and is listed as terminated.
The treatment description specifies intravenous ascorbic acid over 90-120 minutes three times per week, together with oral temozolomide on days 1-28. Treatment was to repeat every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. The registry lists quality-of-life assessment and laboratory biomarker analysis among the interventions. It also lists changes in serum ascorbic acid levels measured using high-performance liquid chromatography with coulometric electrochemical detection, and radiologic measurements for tumor response, as secondary outcomes.
The primary endpoint was a dose-finding safety measure rather than a direct measure of tumor response. The registry says that disease progression left no subjects evaluable for the primary endpoint, and the trial is terminated. The detailed dose levels, dose-escalation procedure, stopping rules beyond the endpoint definition, and reasons for termination beyond disease progression are not reported in the registry record. The registry also does not report a separate control arm, randomization, or a masking procedure. Consequently, the design supports no controlled treatment comparison, and the posted results do not establish an estimated maximum tolerated dose.
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
| Stage | Treatment (Ascorbic Acid, Temozolomide) |
|---|---|
| STARTED | 4 |
| COMPLETED | 0 |
| NOT COMPLETED | 4 |
Reasons for not completing this period:
| Reason | Treatment (Ascorbic Acid, Temozolomide) |
|---|---|
| Lack of Efficacy | 4 |
Analysis population for the primary outcome, as defined in the registry: This study was terminated as subjects had disease progression so no subjects were evaluable.
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.
| Characteristic | Unit | Treatment (Ascorbic Acid, Temozolomide) |
|---|---|---|
| Participants analysed | 4 | |
| Age, Continuous | years | 42 (30 to 64) |
| Sex: Female, Male: Female | Participants | 2 |
| Sex: Female, Male: Male | Participants | 2 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 |
| Race (NIH/OMB): White | Participants | 4 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Region of Enrollment: United States | participants | 4 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose of Ascorbic Acid in Combination With Temozolomide, measured over 56 days.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the maximum tolerated dose of ascorbic acid in combination with temozolomide. It was defined as the highest tested dose at which dose-limiting toxicity occurred in no more than one of six evaluable patients. Toxicities were to be graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. The specified timeframe was 56 days, and the registry says dose-limiting toxicity incidence would be described by dose level.
A maximum tolerated dose endpoint is used in early-phase research to characterize tolerability across tested doses and guide decisions about doses for further study. It is a safety and dose-finding endpoint, not a direct test of whether a regimen improves tumor outcomes. Interpretation depends on the dose levels actually tested, the toxicity observations, and the participants evaluable under the study definition. Those dose-level results are not reported in the registry record.
In this study, the registry states that subjects had disease progression and that no subjects were evaluable. Thus, the endpoint definition is available, but the result needed to identify a maximum tolerated dose is not. The record does not report a dose-limiting toxicity rate by dose level or an estimated maximum tolerated dose. The stated 56-day timeframe does not change that limitation: without evaluable participants, the registry cannot provide an endpoint estimate for that period.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central result is that the planned primary dose-finding endpoint was not evaluable. Four participants enrolled, but the registry states that the study was terminated as subjects had disease progression, so no subjects were evaluable. Therefore, the posted results do not identify a maximum tolerated dose of ascorbic acid in combination with temozolomide. They also do not give a dose-specific estimate of dose-limiting toxicity.
This distinction matters because the study’s primary question was not simply whether any toxicity occurred. The endpoint required evaluable participants at the tested dose levels and a defined toxicity assessment during 56 days. Without evaluable participants, the endpoint rule—no more than one of six evaluable patients experiencing dose-limiting toxicity at the highest tested dose—cannot be applied to produce a dose estimate. The dose levels, detailed dose-escalation process, and dose-specific toxicity results are not reported in the registry record.
The registry lists four participants at risk for serious adverse events, two participants affected by serious adverse events, one affected by other adverse events, and zero deaths in the treatment group. The listed serious adverse event terms are headache, vomiting, hyponatremia, seizure, pain in the hip or back, and weakness, each reported as 25.0%. These safety figures describe events recorded in the group; they do not supply the missing primary dose-finding result. The registry does not report detailed event timing, severity grades, relationship to treatment, or event counts for each listed term.
The design is single-group and unmasked, with no separate comparator. As a general statistical point, a single-group study describes outcomes among participants receiving the study regimen but cannot isolate the regimen’s effects from other influences through a concurrent between-group comparison. This is especially important for tumor response and other outcomes that can change over time. The listed secondary outcomes do not have posted analysis results in the registry record.
No confidence interval, p-value, or estimate of treatment effect for the primary endpoint is reported. A confidence interval generally communicates the range of values compatible with data under a statistical model; it cannot remedy the absence of evaluable endpoint data. The record lists zero analyses. The appropriate reading is therefore limited: the registry records enrollment, termination, the reason subjects were not evaluable, and a small set of adverse-event summaries, but it does not report an estimated maximum tolerated dose or a comparative efficacy result.
Any accompanying sample-size calculations are planning illustrations, not observed power and not the study’s original design justification. Their stated assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and a target effect defined as a fraction of the observed effect. Those assumptions describe a hypothetical planning exercise and do not match this study’s single-group design. The registry does not report an original sample-size justification.
9. Statistical Methods Explained
The study’s statistical purpose was dose finding. In an early-phase dose-finding study, investigators assess tolerability at dose levels and use the observed toxicity pattern to identify a dose for consideration in later research. This is different from a randomized comparison intended to estimate a treatment difference. Here, the registry identifies one treatment group and defines the primary endpoint in terms of the highest tested ascorbic acid dose meeting a dose-limiting toxicity rule.
What does the endpoint rule mean?
The registry defines the maximum tolerated dose as the highest dose tested that results in dose-limiting toxicity in no more than one of six evaluable patients. This is a rule for classifying dose-level observations, not a result by itself. Applying it requires information about which doses were tested, which participants were evaluable at each dose, and which toxicities met the dose-limiting definition. The record says toxicities were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 and that incidence would be described by dose level. The dose levels and dose-specific observations are not reported in the registry record.
The 56-day timeframe defines the stated period for the primary endpoint. In general, a fixed assessment period gives a common window for determining whether the outcome has occurred. It does not make incomplete or unavailable outcome data equivalent to an absence of toxicity. In this trial, the registry explicitly states that disease progression meant no subjects were evaluable. The endpoint therefore cannot be interpreted as showing that dose-limiting toxicity did not occur; it is not evaluable.
Why does the design matter?
The record identifies a single-group study, allocation as NA, and masking as none. There is no separate group receiving a comparator regimen. General statistical interpretation of a single-group study is descriptive: observations can characterize the participants who received the regimen, but they do not provide a concurrent control for separating treatment effects from other influences. The absence of a control is particularly relevant to outcomes such as radiologic tumor response, because a change observed over time in one group is not by itself a comparative treatment effect.
Masking concerns whether participants or study personnel know which intervention is assigned. The registry lists no masking. The record does not report further details about how outcomes were assessed or whether any assessment procedures were blinded. It also does not report randomization, an allocation procedure, a dose-escalation method, or a statistical analysis plan. These details should not be inferred from the phase or the dose-finding endpoint definition.
What can adverse-event summaries show?
Adverse-event counts and listed terms describe safety observations recorded in the study group. They are not automatically estimates of comparative risk, because there is no comparison group. General interpretation also requires care about denominators and whether a summary counts participants with an event or total event occurrences. The registry reports the number at risk and affected for serious and other adverse events, and lists serious adverse event terms with percentages. It does not report detailed event counts, event timing, severity grades, or treatment relationship for each term. The terms and percentages should therefore be read as the registry’s reported summaries, not as a complete causal assessment.
What do the planning assumptions represent?
Any sample-size figures associated with planning are illustrations rather than results from this trial. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is described as a fraction of the observed effect. General sample-size calculations ask how much information a hypothetical design might need under chosen assumptions. They do not show that a study had that number of participants, that its original plan used those assumptions, or that it achieved a particular probability of detecting an effect. Sample sizes are planning illustrations, never observed power. The assumptions of two arms and equal allocation also do not describe the actual single-group design.
The record does not provide an observed primary endpoint effect on which to base a clinical efficacy interpretation. The record lists zero analyses, and the stated primary endpoint was not evaluable. Thus there is no posted estimate, confidence interval, or p-value for the primary outcome. In general, a confidence interval expresses uncertainty around an estimate under specified assumptions, while a p-value summarizes how data compare with a statistical null model. Neither statistic can be interpreted as a substitute for endpoint observations that are not reported.
Over-dispersion is a general issue when outcome variability exceeds what a chosen statistical model assumes; it can make model-based uncertainty too small if not handled appropriately. The registry does not report a count model, an over-dispersion assessment, or a statistical analysis plan that would allow such a method to be evaluated. No particular model or adjustment should be attributed to this study based on the information in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists a primary endpoint focused on maximum tolerated dose and secondary outcomes involving changes in serum ascorbic acid levels and radiologic tumor response. It also lists quality-of-life assessment and laboratory biomarker analysis among the interventions. There are four outcome measures recorded, but the specific details for all measures and their analyses are not presented in the registry record. No analyses are listed.
When a study examines multiple outcomes or multiple comparisons, general statistical practice considers whether the chance of finding an apparently notable result through repeated testing needs to be addressed. Such approaches are commonly called multiplicity control. The record does not report a multiplicity adjustment, a hierarchy of outcome testing, or a prespecified strategy for handling several outcomes. It would not be appropriate to assume that any particular adjustment was or was not used outside what is recorded.
Missing outcome information is central to interpretation. The registry states that subjects had disease progression and that no subjects were evaluable for the primary endpoint. It does not report how many participants had data for each secondary outcome, whether any assessments were completed before progression, or how missing observations were handled. In general, missing outcome data can limit both the precision and the interpretation of estimates; the reason and pattern of missingness matter. Here, the stated lack of evaluable participants means the primary endpoint estimate is unavailable, rather than an estimate of no toxicity.
The registry does not describe analysis populations, such as which enrolled participants would be included for each endpoint, beyond stating that no subjects were evaluable for the primary measure. It also does not report imputation methods, sensitivity analyses, or an analysis plan. These omissions prevent assessment of how incomplete data or differing eligibility for outcome analyses would have been handled.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Treatment (Ascorbic Acid, Temozolomide) | 2 | 4 | 50.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Treatment (Ascorbic Acid, Temozolomide) | 0 of 4 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Treatment (Ascorbic Acid, Temozolomide) | 1 of 4 |
Most frequent serious adverse event terms
| Event term | Organ system | Treatment (Ascorbic Acid, Temozolomide) |
|---|---|---|
| Headache | General disorders | 1 of 4 |
| Vomiting | Gastrointestinal disorders | 1 of 4 |
| Hyponatremia | Metabolism and nutrition disorders | 1 of 4 |
| Seizure | Nervous system disorders | 1 of 4 |
| Pain, Hip, back | Musculoskeletal and connective tissue disorders | 1 of 4 |
| Weakness | General disorders | 1 of 4 |
| Urinary retention | Renal and urinary disorders | 1 of 4 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Treatment (Ascorbic Acid, Temozolomide) |
|---|---|---|
| Lymphopenia | Blood and lymphatic system disorders | 1 of 4 |
| Hyponatremia | Metabolism and nutrition disorders | 1 of 4 |
Serious events with the highest arm-level rate: headache (25.0%), vomiting (25.0%), hyponatremia (25.0%), seizure (25.0%), pain, hip, back (25.0%).
The registry reports one treatment group with four participants at risk for serious adverse events and two affected by serious adverse events. It reports four participants at risk for other adverse events and one affected. The group has zero deaths recorded. These are counts of participants at risk and affected in the registry summary; they do not establish that every listed event was caused by treatment.
The serious adverse event terms listed are headache, vomiting, hyponatremia, seizure, pain in the hip or back, and weakness. Each term is reported as 25.0%. The registry does not provide the event count or timing for each term, severity grade, duration, outcome, or relationship to study treatment. The listed percentages should therefore be interpreted as reported term-level summaries, not as a complete account of event frequency or a comparison of risks.
In general, adverse-event summaries are descriptive, and their meaning depends on definitions, observation time, and the way events are counted. The registry does not report further details needed to assess those aspects for each event. With no comparator group and only four participants enrolled, these summaries cannot establish a comparative safety profile. They also do not replace the primary endpoint’s dose-specific assessment of dose-limiting toxicity, which was not evaluable.
12. What the Result Does, and Does Not, Mean
The registry record documents a phase I, single-group study of intravenous ascorbic acid with oral temozolomide in recurrent high-grade glioma. It records four participants enrolled and says the study was terminated after subjects had disease progression. No subjects were evaluable for the primary endpoint. This is the defining result for interpreting the study’s dose-finding question: the posted record does not establish a maximum tolerated dose.
The record does not show that the regimen was effective or ineffective. Although radiologic tumor response was listed as a secondary outcome, no analysis results are reported. The primary endpoint was dose-limiting toxicity and maximum tolerated dose, not a comparative assessment of tumor control. A missing estimate is not evidence of a particular clinical effect.
Nor can the safety summaries determine whether an event was caused by either study drug. The registry reports serious and other adverse-event counts, listed serious event terms, and no deaths, but it does not report detailed attribution, grading, timing, or comparative data. The single-group design does not distinguish events associated with the regimen from events that might occur for other reasons in the study population.
General statistical interpretation distinguishes the observed information from the conclusions a design can support. A controlled comparison can help estimate differences between groups under its assumptions; this study had no separate comparator. An endpoint estimate also requires evaluable outcome data; the registry says none were available for the primary measure. These limitations mean the record can describe what was planned, who enrolled in aggregate, why the primary endpoint was not evaluable, and the adverse-event summaries, but it cannot answer the primary dose question or establish a treatment effect.
The study’s termination and lack of evaluable participants should not be recast as a completed dose-finding result. No maximum tolerated dose, dose-specific toxicity estimate, or primary endpoint confidence interval is reported. The registry record also does not report a statistical analysis plan or explain how the listed secondary outcomes were analyzed. Interpretation should remain within these documented limits.
13. Why This Trial Matters Statistically
This study illustrates why early-phase dose-finding questions depend on evaluability at the tested doses. The endpoint was not a general count of adverse events; it used a dose-specific rule and a defined toxicity assessment period. The registry states that disease progression left no subjects evaluable, so the planned rule cannot yield a maximum tolerated dose from the posted record. Recognizing the distinction between an endpoint definition and an endpoint result is essential when reading trial registries.
It also highlights the difference between safety summaries and a dose-finding conclusion. The record reports participants affected by serious and other adverse events and lists serious event terms, but those summaries do not provide the dose-level observations required by the primary endpoint. They also do not give a controlled comparison or establish treatment attribution. A safety count, a dose-limiting toxicity assessment, and an estimate of maximum tolerated dose are related but not interchangeable pieces of evidence.
The single-group design further defines what can be learned. Descriptive results can report observations among participants who received the regimen, but without a comparator they cannot estimate a between-group treatment difference. This is relevant to the listed radiologic response outcome as well as to the interpretation of adverse events.
Finally, the record demonstrates why planned sample-size illustrations should not be confused with study results or original design assumptions. The stated planning assumptions involve two arms and equal allocation, unlike the recorded single-group design. Such illustrations do not restore missing primary outcome data, create an observed effect, or establish observed power. Clear separation of design, endpoint definition, available observations, and hypothetical planning helps prevent claims that go beyond the registry record.
14. 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 principal limitation is that the primary endpoint was not evaluable. The registry attributes this to disease progression and states that no subjects were evaluable. As a result, the record does not report a maximum tolerated dose or dose-limiting toxicity incidence by dose level. The detailed dose levels and the number of participants assessed at each dose are not reported in the registry record.
Only four participants enrolled, and the study is listed as terminated. This limits the amount of outcome information available in the registry, but the record does not provide a completed primary endpoint estimate for which precision could be assessed. No confidence interval or other uncertainty measure for the primary outcome is reported. The registry does not give further details about timing of progression or how it affected individual outcome assessments.
The single-group design and absence of masking mean there is no concurrent comparator in the record. Consequently, there is no direct basis for estimating a comparative treatment effect, and the adverse-event summaries cannot establish comparative safety. The registry does not report a detailed dose-escalation scheme, the exact dose levels tested, the statistical analysis plan, a sample-size justification, interim analyses, or analysis populations beyond the statement that no subjects were evaluable for the primary endpoint.
Secondary outcomes are listed, but their analysis results and completeness are not reported. The registry does not describe missing-data methods, multiplicity handling, event attribution, adverse-event severity grades, or detailed event timing. These limitations restrict interpretation of both the planned secondary outcomes and the safety summaries. They should not be filled in by assuming methods or results that are absent from the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Temozolomide and Ascorbic Acid in Treating Patients With Recurrent High-Grade Glioma — NCT02168270.
- Registry record last updated 2023-11-24; status last verified 2023-11.
- Results first posted 2018-02-23.
- 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.
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18. Record Summary
NCT02168270 is a phase I, single-group study sponsored by the University of Nebraska of intravenous ascorbic acid with oral temozolomide for recurrent high-grade glioma. The registry lists an enrollment of four, a start date of 2014-06-16, a primary completion date of 2015-08-20, and a terminated status.
The primary endpoint was maximum tolerated dose over 56 days, defined using dose-limiting toxicity graded under the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. The registry states that subjects had disease progression and no subjects were evaluable, so no maximum tolerated dose is reported. The record includes summaries of serious and other adverse events, but no analyses are listed. It does not report a comparator group, a treatment-effect estimate, or results for the listed secondary outcomes.