Temozolomide 12 Cycles Versus 6 Cycles of Standard First-line Treatment in Patients With Glioblastoma.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Temozolomide 12 Cycles Versus 6 Cycles of Standard First-line Treatment in Patients With Glioblastoma. (NCT02209948), a randomized phase 2 study. The primary outcome is Progression Free Survival at 6 Month.

2. Clinical Question

The central comparison is between continuing temozolomide and stopping after the first six cycles. The primary endpoint focuses on progression status at a specified time point, while the secondary outcomes include progression-free survival and overall survival over the study follow-up, as well as selected outcomes by MGMT methylation status and adverse effects.

The posted primary results are percentages of participants without progression at six months. The Temozolomide arm had 61.3% (95% confidence interval 51.5 to 72.9), and the Without Treatment arm had 55.7% (95% confidence interval 45.8 to 67.8). These estimates describe the trial participants and have uncertainty, as reflected by their confidence intervals. The registry record also posts an unadjusted comparison with p = 0.477; that statistic does not by itself establish whether the arms differ in a clinically important way.

The trial therefore addresses a specific continuation question in the randomized participants. Its results do not automatically answer questions about other treatment schedules, populations, or outcomes that were not measured or reported in the registry record.

3. Trial Design

This was a Phase 2, randomized, parallel-group trial with no masking, listed as completed. The registry record reports enrollment of 166 participants. The study compared six additional cycles of temozolomide with no further treatment after the first six cycles of standard first-line treatment.

The record describes randomization according to MGMT methylation status and the presence or absence of residual disease. It does not report the randomization method, allocation concealment, or whether any additional stratification or balancing procedures were used. With no masking, participants and study personnel were not masked to the assigned treatment, according to the registry entry. The record does not specify whether outcome assessors were masked.

For the primary endpoint, the posted arm counts are 80 for Temozolomide and 79 for Without Treatment. These counts differ from the enrollment total, but the reasons and the endpoint analysis population are not reported in the registry record. The posted overall survival results use the same arm counts. The subgroup results by MGMT methylation status list 49 and 48 participants in each respective comparison. The record does not explain the relationship between these subgroup counts and the full randomized groups.

The primary outcome was progression-free survival at six months, expressed as the percentage of participants without progression. Secondary outcomes include median progression-free survival, overall survival, results by MGMT methylation status, adverse effects, and a translational biomarker sub-study. The registry record lists seven outcome measures and reports six secondary outcomes. The specific protocol, original statistical analysis plan, sample-size justification, and planned analysis populations are not reported in the registry record.

The study began on 2014-08-22, with primary completion listed as 2019-06. The median follow-up for each patient is reported as 33.4 months for the secondary time-to-event outcomes. The registry record does not give the precise follow-up schedule or the timing of each analysis.

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: 7 patients do not meet inclusion criteria. Only 159 patients were randomized

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 Progression Free Survival at 6 Month, measured over 6 month.

The primary endpoint is progression-free survival at six months, reported as the percentage of participants without progression at that time. The registry description also defines progression-free survival as the time from randomization to progression, with progression determined according to RANO criteria. The six-month percentage reduces that time-to-event information to a status at a particular point: whether a participant had remained without documented progression up to that point.

A fixed-time percentage can be easier to interpret than a full survival curve because it directly describes the proportion without progression at a clinically specified time. It also has limitations. It does not show when events occurred before or after the selected time point, and it does not convey the full pattern of follow-up or censoring. Participants whose status at the time point is unavailable may also affect the estimate, depending on the analysis approach; how missing or censored observations were handled is not reported in the registry record.

The posted primary estimates are 61.3% (95% confidence interval 51.5 to 72.9) for Temozolomide and 55.7% (95% confidence interval 45.8 to 67.8) for Without Treatment. The endpoint’s reported unit is percentage of patients, and the timeframe is six months. The confidence intervals express uncertainty around each arm estimate; they do not describe the range of outcomes for individual participants.

As a general statistical point, a fixed-time endpoint is most informative when its event definition, time origin, and handling of incomplete follow-up are clear. The time origin and progression criteria are stated, but further analysis details are not reported in the registry record.

7. Results Posted in the Registry

• Without Treatment: 55.7% (44/79) versus 61.3% (49/80) on control; risk difference -5.6 percentage points (95% CI -20.8 to 9.7), risk ratio 0.91 (0.70–1.18); unadjusted two-proportion z-test p = 0.477.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Overall Survival

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Regression, Cox); it was not recalculated.
• Result:
  • Temozolomide vs Without Treatment: hazard ratio 1.30 (95% CI 0.90–1.88), reported p = 0.160 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Temozolomide vs Without Treatment and the control. The interval gives the range of effects that remain compatible with the data.

Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Regression, Cox); it was not recalculated.
• Result:
  • Temozolomide vs Without Treatment: hazard ratio 1.00 (95% CI 0.65–1.50), reported p = 0.990 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Temozolomide vs Without Treatment and the control. The interval gives the range of effects that remain compatible with the data.

Median Overall Survival (OS) by Arm and MGMT Methylation Status

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Regression, Cox); it was not recalculated.
• Result:
  • Temozolomide vs Without Treatment: hazard ratio 1.45 (95% CI 0.89–2.33), reported p = 0.130 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Temozolomide vs Without Treatment and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the assessment beyond the six-month progression-free status. They include median progression-free survival and overall survival, with additional comparisons by MGMT methylation status, as well as adverse effects and a biomarker sub-study. Collectively, they describe different aspects of follow-up and safety, but they do not all measure the same underlying quantity as the primary endpoint.

The posted secondary time-to-event comparisons do not present a uniform, definitive separation between the arms. Their estimates have confidence intervals that include the reference value of 1, and the reported p-values are not small. Taken together with the primary result, the registry results leave uncertainty about differences between the treatment strategies rather than confirming a clear pattern across endpoints. The subgroup analyses add further exploratory detail, but their smaller posted counts and lack of reported interaction testing constrain interpretation.

Secondary outcomes often carry less weight than a prespecified primary endpoint because there may be many opportunities to examine different outcomes, time points, or subgroups. When multiple comparisons are made, the chance of observing an apparently notable result by chance can increase. Adjustment procedures or a hierarchy of testing can address this concern, but multiplicity methods and the prespecified status of these analyses are not reported in the registry record.

These secondary findings should therefore be considered supportive or exploratory rather than treated as independent confirmation of a treatment effect. Their interpretation also depends on analysis details such as censoring, missing data, and outcome definitions, which are not fully described in the registry record. The overall pattern is best read alongside the primary endpoint and with attention to the broad uncertainty in the estimates, not as a collection of isolated p-values.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Participants With Adverse Effects
• Progresion Free Survival Median Values
• Overall Survival
• Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status
• Median Overall Survival (OS) by Arm and MGMT Methylation Status
• Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity

9. Statistical Interpretation

10. Statistical Methods Explained

The registry record reports several kinds of statistics. They answer different questions and should not be treated as interchangeable: an arm percentage describes an observed proportion at a specified time, a median describes the middle of a time-to-event distribution, a hazard ratio compares event rates over follow-up under a model, and a confidence interval describes uncertainty around an estimate.

What does a confidence interval describe?

In general, a confidence interval is a range of values compatible with the observed data under a specified statistical procedure. It captures sampling uncertainty, not the range of outcomes among individual participants, and it does not account for every possible source of bias or error. The primary arm-specific intervals are 51.5 to 72.9 for Temozolomide and 45.8 to 67.8 for Without Treatment. The comparison interval for the risk difference is -0.208 to 0.097. Because that interval includes zero, the posted estimate does not rule out no difference under the comparison method. It also includes estimates in either direction.

Confidence intervals can be more informative than a p-value alone because they show the scale and precision of estimates. Their interpretation still depends on the statistical method and assumptions. The registry record identifies the confidence level as 95% for the posted intervals, but it does not give all details of the methods used to calculate the primary interval.

How should the risk difference and p-value be read?

The risk difference compares the proportions in two arms. The reported estimate is -0.056 for the comparison of Without Treatment with Temozolomide. Its sign follows that order; it should not be detached from the comparator definition. The unadjusted p-value is 0.477. In general, a p-value measures how incompatible the observed data are with a specified null model, given the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of an effect.

The registry record labels this comparison unadjusted. It does not report adjustment for covariates, multiplicity, or the details of the statistical test for this primary comparison. The p-value should therefore be understood as the posted unadjusted result, not as a complete account of all possible analyses.

What do medians and hazard ratios mean?

A median time-to-event estimate is the time by which half of the relevant group has experienced the event, subject to the analysis and follow-up methods. The overall survival medians are 18.2 months and 23.3 months for the two arms. Medians compress the follow-up distribution to one point and can obscure differences in the timing of events elsewhere in that distribution.

A hazard ratio compares the event rate over time between groups under a time-to-event model. A value of 1 corresponds to equal hazards under that model; values above or below 1 indicate a relative direction that depends on which arm is in the numerator. The registry record reports Cox regression for the secondary overall survival and MGMT subgroup comparisons. For overall survival, the comparison is Temozolomide versus Without Treatment, with hazard ratio 1.30 (95% confidence interval 0.90 to 1.88) and p = 0.16. A hazard ratio is not a ratio of medians, and it does not directly state how many months participants lived.

General interpretation of a Cox hazard ratio relies on model assumptions, including an appropriate representation of the relative hazards over follow-up. The registry record does not report diagnostics or whether the proportional-hazards assumption was assessed. It also does not report details of censoring or the precise analysis population for these models.

Why does over-dispersion matter?

General explanation: for a binary outcome, a simple model may assume that observed variation is adequately described by the binomial distribution. Over-dispersion means the data vary more than that model expects. If present and ignored, uncertainty estimates can be too small and tests can appear more decisive than warranted. The registry record does not report an assessment of over-dispersion for the primary endpoint, so it is not possible to say whether it was present or how it was handled.

What is the role of subgroup analysis?

Subgroup estimates can explore whether patterns differ across participant characteristics, but smaller groups usually provide less precise estimates. The posted MGMT methylation-status comparisons include 49 and 48 participants per arm. A subgroup-specific result is not itself evidence that the treatment effect differs between subgroups; that question generally requires a treatment-by-subgroup interaction analysis. The registry record does not report such an interaction test or whether subgroup analyses were specified before examining the results.

In general, statistical interpretation also depends on choices that may not be visible in summary estimates: eligibility and analysis populations, missing-data rules, censoring definitions, covariate adjustment, and multiplicity procedures. These details are not reported in the registry record. The estimates can be described as posted, but the absent details limit an independent assessment of the analysis plan and its execution.

11. Confidence Intervals and Precision

The confidence intervals show that the arm-specific primary estimates are not highly precise. The Temozolomide estimate is 61.3%, with a 95% confidence interval from 51.5 to 72.9; the Without Treatment estimate is 55.7%, with a 95% confidence interval from 45.8 to 67.8. Each interval covers a range of plausible values for its arm-level percentage under the interval method. These ranges should not be interpreted as individual outcomes or as guarantees about the true value.

The direct comparison is more useful for assessing the difference between arms than comparing the arm-specific intervals by eye. Its risk-difference estimate is -0.056, with a 95% confidence interval from -0.208 to 0.097. The interval includes zero and also permits estimates in either direction. Thus, the result is not precise enough to distinguish a range of possible differences from no difference. This uncertainty should be kept in view alongside the p-value of 0.477.

The secondary time-to-event estimates also have broad confidence intervals. For overall survival, the hazard ratio is 1.30, with an interval from 0.90 to 1.88. The subgroup hazard-ratio intervals are 0.65 to 1.5 for progression-free survival and 0.89 to 2.33 for overall survival. These intervals span values on both sides of 1, the reference value for equal hazards. The subgroup counts are smaller than the full-arm counts, which is relevant when considering their precision.

As a general principle, interval width reflects statistical uncertainty under the method used, not all uncertainty about the study. Bias, incomplete follow-up, outcome measurement, and model assumptions may contribute additional uncertainty. The registry record does not report enough detail to assess all of these factors. The intervals are therefore important, but they are not a complete guarantee of reliability.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The displayed sample-size figures are planning illustrations based on the observed effect, not the trial’s original design assumptions. The registry record states that the illustrations use a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. For binary comparisons, figures are participants per arm. For time-to-event comparisons, figures are total events.

The 80% power column gives the illustrative number of participants per arm, or total events for time-to-event outcomes, that would be needed for an 80% chance of detecting the specified effect under those assumptions if that effect were real. The 90% power column gives the corresponding planning quantity for a 90% chance. These are design calculations, not observed outcomes, and they do not describe the probability that the trial’s conclusion is correct.

For the primary binary comparison, the figures are 1,235 participants per arm for 80% power and 1,653 per arm for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 2,185 per arm for 80% power and 2,925 for 90% power. Planning for 50% gives 4,891 and 6,547 per arm, respectively. The time-to-event illustrations are expressed as total events rather than participants per arm; for example, the overall survival comparison gives 457 total events for 80% power and 611 for 90% power when planning for 100% of the observed effect.

Smaller effects are harder to distinguish from random variation, so planning to detect a smaller fraction of the observed effect requires more participants or events. These calculations are not observed power. The original trial’s sample-size justification and design assumptions are not reported in the registry record, so the illustrations should not be mistaken for the trial’s planned enrollment target or its achieved ability to detect an effect.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.613; treatment proportion p₁ = 0.557; average p̄ = 0.585.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6969 = 1.3659.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6958 = 0.5856.
4. n = (1.3659 + 0.5856)² / (-0.0555)² = 1,234.6, rounded up to 1,235 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.6125                          # control proportion
p1 <- 0.556962025316456                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2209948)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 1,235 (80% power), 1,653 (90% power)
 75% of observed effect: n per arm = 2,185 (80% power), 2,925 (90% power)
 50% of observed effect: n per arm = 4,891 (80% power), 6,547 (90% power)
power.prop.test: 1234.6 
Simulated power at n = 1,235 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists several outcomes and multiple analyses, including the primary six-month progression-free endpoint, survival outcomes, subgroup results by MGMT methylation status, adverse effects, and a biomarker sub-study. It does not report whether the secondary analyses were prespecified, whether a testing hierarchy was used, or whether p-values were adjusted for multiple comparisons. Without that information, the chance of false-positive findings across the set of analyses cannot be assessed from the posted results alone.

Missing-data handling is also not reported. The primary outcome lists 80 participants in the Temozolomide arm and 79 in the Without Treatment arm, while enrollment is 166. This difference does not by itself establish that data were missing or that participants were excluded; the registry record does not explain the counts or define the primary analysis population. It does not say how participants without an observed six-month status were handled, whether an intention-to-treat population was used, or whether any sensitivity analyses were conducted.

For time-to-event outcomes, the registry record reports a median follow-up of 33.4 months for each patient. It does not provide details on censoring rules, loss to follow-up, or how incomplete observation was addressed. These choices matter because participants who have not experienced an event by the end of observation contribute differently from participants with a recorded event.

The record also does not report the original statistical analysis plan, interim analyses, stopping rules, covariate-adjustment strategy, or analysis populations. The absence of these details should not be taken as evidence that a particular procedure was or was not used. It means that the posted registry results do not permit a full audit of multiplicity control, missing-data assumptions, or analysis decisions. These limitations are relevant to both the primary result and the interpretation of secondary and subgroup findings.

15. 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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neurological impairment (2.5%), dysarthria (1.3%), syncope (1.3%), dyspnoea (1.3%), general deterioration (1.3%).

For serious adverse effects, the registry record lists 9 affected participants among 80 at risk in the Temozolomide arm and 5 among 79 at risk in the Without Treatment arm. It also lists other adverse effects for 80 of 80 and 79 of 79 participants, respectively. These counts describe the posted registry entries; they do not establish that an event was caused by the assigned treatment.

The record lists 63 deaths in the Temozolomide arm and 52 in the Without Treatment arm. It does not report the causes of death or attribute them to treatment. Death counts should therefore not be interpreted as treatment-related adverse effects on the basis of this entry alone.

The most frequently listed serious event terms include neurological impairment at 2.5%, and dysarthria, syncope, dyspnoea, general deterioration, and pulmonary embolism at 1.3% each. The registry record does not give further detail about timing, severity grading, duration, or the attribution process for these terms. The serious-event figures should be read as descriptive counts, with those reporting limitations in mind. They do not provide a complete comparative safety analysis or a basis for individual medical decisions.

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

The randomized comparison provides evidence about the posted outcomes among participants assigned to six additional cycles of temozolomide or no further treatment after the first six cycles. The primary result is a six-month percentage without progression, accompanied by an unadjusted comparison whose confidence interval includes no difference. The registry record therefore does not establish a clear between-arm difference for this endpoint, while also not proving that the strategies are equivalent.

Secondary survival estimates provide additional information about follow-up but remain uncertain. Medians and hazard ratios summarize different features of time-to-event data; neither should be read as a complete description of every participant’s outcome. The subgroup estimates by MGMT methylation status are based on smaller counts, and the registry record does not report an interaction test. They cannot by themselves establish that the relative effect differs across methylation groups.

These results do not show that an effect is exactly absent. A confidence interval can include no difference while also allowing potentially meaningful effects in either direction. Nor do the results establish that any observed outcome was caused by treatment. Randomization supports a comparison of assigned strategies, but interpretation still depends on appropriate conduct, follow-up, endpoint measurement, and analysis.

The registry record does not report the original sample-size rationale, detailed missing-data rules, multiplicity plan, or full analysis populations. Those omissions limit how thoroughly the posted estimates can be evaluated. The results apply most directly to the trial population and treatment contrast described in the record; they should not be generalized automatically to other populations, schedules, or clinical contexts.

In short, the posted outcomes show uncertain estimates rather than a conclusive demonstration of benefit, harm, or equivalence. They describe what was recorded in this randomized study and how precisely the results were estimated, but they do not settle every question about treatment continuation or safety.

17. Why This Trial Matters Statistically

This trial is statistically useful because it evaluates a specific continuation decision with randomized allocation. Randomization can reduce systematic differences between assigned groups at baseline, making the comparison more informative than an uncontrolled comparison, although it does not eliminate uncertainty or resolve problems in follow-up and analysis. The parallel-group design also makes the treatment strategies explicit: additional temozolomide cycles versus stopping further treatment after the first six cycles.

The primary endpoint illustrates why both effect estimates and precision matter. An arm-level percentage alone does not show how uncertain a comparison is. The posted risk-difference interval includes zero and a range of values in both directions, so the result should not be reduced to a binary claim based only on its p-value. The confidence interval gives a clearer view of the limits of what these data distinguish.

The registry results also demonstrate the difference between a primary question and a larger collection of secondary outcomes. Survival measures, subgroup analyses, and adverse-effect counts can provide context, but multiplicity and smaller subgroup sizes make isolated findings less secure. Without the original analysis plan and multiplicity details, the reader cannot determine how these analyses were prioritized.

Finally, the planning illustrations show how strongly sample-size needs depend on the effect one aims to detect. Their large values relative to the posted enrollment emphasize that a trial can produce broad intervals when the observed effect is modest or the available information is limited. These figures are retrospective planning illustrations, not evidence that the trial was designed around them. The distinction between study design, observed results, and post hoc planning is important for sound statistical interpretation.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several trial-specific limitations affect interpretation of the registry results. The study was unmasked, so participants and study personnel knew the assigned arm. The registry record does not say whether outcome assessors were masked or what safeguards were used for subjective assessments. The primary endpoint uses a defined progression criterion, but further information about assessment timing and adjudication is not reported.

The primary endpoint counts and the overall enrollment total do not fully align, and the registry record does not explain the difference. No analysis population is specified, and handling of missing or unavailable six-month progression status is not reported. These omissions make it difficult to assess whether the posted arm counts represent all randomized participants or a defined subset.

The record reports median follow-up of 33.4 months for each patient for secondary survival outcomes, but does not describe censoring, follow-up completeness, or the number of events underlying the time-to-event analyses. It also does not provide the original sample-size justification, full statistical analysis plan, interim-analysis history, or multiplicity procedures. These details are important for judging precision and the risk of selective interpretation.

The MGMT subgroup outcomes have smaller posted arm counts than the overall analyses. The record does not state whether subgroup comparisons were prespecified or report a treatment-by-subgroup interaction analysis. The subgroup estimates therefore have limited support for claims about differing treatment effects by methylation status.

Safety reporting is also incomplete for detailed comparative interpretation. The registry lists affected-participant counts, event terms, and deaths, but does not provide event timing, severity grading, attribution, or causes of death. These specific limitations do not negate the posted results, but they constrain what can be concluded from them.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Temozolomide 12 Cycles Versus 6 Cycles of Standard First-line Treatment in Patients With Glioblastoma. — NCT02209948.
• Registry record last updated 2021-01-12; status last verified 2020-12.
• Results first posted 2021-01-12.
• 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.

22. Record Summary

The registry record describes a completed, Phase 2, randomized, parallel-group trial of six additional cycles of temozolomide versus no further treatment after six cycles of standard first-line treatment for glioblastoma. Enrollment was 166, and the study was unmasked.

The primary outcome was the percentage of participants without progression at six months, with progression defined according to RANO criteria. The posted percentages were 61.3% for Temozolomide and 55.7% for Without Treatment. The unadjusted risk-difference comparison has a 95% confidence interval that includes zero.

Secondary outcomes include progression-free survival, overall survival, subgroup results by MGMT methylation status, adverse effects, and a biomarker sub-study. The registry record reports Cox regression for secondary time-to-event comparisons and a median follow-up of 33.4 months. Important design and analysis details, including the original sample-size justification, missing-data handling, and multiplicity plan, are not reported in the registry record. The posted estimates should be interpreted with their uncertainty and reporting limitations in mind.