Everolimus With and Without Temozolomide in Adult Low Grade Glioma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Everolimus With and Without Temozolomide in Adult Low Grade Glioma (NCT02023905), a non-randomized phase 2 study. The primary outcome is Progression-Free Survival Rate (PFS) (Arms 1 and 2).

2. Clinical Question

The study’s broader purpose was to examine the effects of everolimus, alone or combined with temozolomide, in people with low-grade glioma. Its treatment allocation was based on tumor features rather than random assignment. Arm 1 used everolimus for tumors with intact 1p/19q and PI3K/mTOR pathway activation; Arm 2 used everolimus with temozolomide for tumors with intact 1p/19q and no pathway activation. Arm 3 used everolimus for tumors with 1p/19q co-deletion. These are clinically defined groups, not interchangeable treatment arms. The primary endpoint named in the record concerns Arms 1 and 2, while the registry also lists secondary outcomes of median progression-free survival, overall survival rate, objective response rate, and reduction in seizures.

3. Trial Design

This was a phase II, parallel-group study with non-randomized allocation and no masking. The recorded enrollment was 27. The sponsor was the University of California, San Francisco. The study started on 2014-03-19, had a primary completion date of 2021-09-30, and is listed as terminated. The reason for termination is not reported in the registry record.

Three treatment groups are described. Arm 1 received single-agent everolimus following selection based on intact 1p/19q and evidence of PI3K/mTOR pathway activation. Arm 2 received everolimus with temozolomide when 1p/19q was intact and pathway activation was not present. Arm 3 received single-agent everolimus when 1p/19q co-deletion was present. The registry’s arm descriptions are truncated, so further details of treatment duration or follow-up beyond the text recorded are not reported in the registry record.

Because assignment was not randomized, comparisons between arms can reflect differences in tumor biology, eligibility, or other characteristics associated with treatment selection, as well as any treatment-related differences. The record explicitly cautions that the arms are not a like-for-like control comparison. The primary outcome was specified for Arms 1 and 2, with progression-free survival assessed up to 33 months. The record describes intention-to-treat analysis and separate Kaplan–Meier estimates for those two arms. It does not report a randomized treatment contrast or a statistical test comparing them.

The registry lists six outcome measures and zero posted analyses. The primary outcome result is not reported in the registry record. Details such as the reason for the non-randomized allocation, a sample-size justification, or the reason the study was terminated are 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

Analysis population for the primary outcome, as defined in the registry: One participant in Arm 2 went off treatment after only a few days of beginning therapy but was included in the analysis as part of the ITT population

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 Rate (PFS) (Arms 1 and 2), measured over Up to 33 Months.

The primary endpoint is the progression-free survival rate for Arms 1 and 2, assessed through 33 months. In general, progression-free survival describes the time participants remain alive without disease progression; an estimate at a specified follow-up time expresses the estimated proportion still free of the defined event by that time. The registry specifies RANO criteria for determining progression and says that radiographic and clinical criteria are considered. It describes radiographic assessment of tumor-size change and consideration of neurologic function and steroid use. It does not give further operational detail about how each criterion was combined to classify progression.

The registry planned to estimate progression-free survival separately in each arm using Kaplan–Meier methods, with an associated 95% confidence interval. Kaplan–Meier estimation is used for time-to-event outcomes because participants can have different follow-up durations, including follow-up that ends before an event is observed. The estimate at a fixed time is therefore not simply a raw fraction of all enrolled participants. The posted primary outcome result, including the arm-specific estimates and their confidence intervals, is not reported in the registry record.

Progression-free survival is used in clinical studies to describe disease control over time without relying only on a single tumor measurement. It is distinct from objective response rate, which the registry lists as a secondary outcome. A response and remaining progression-free are related but not identical concepts: a participant may have stable disease without meeting response criteria. The registry does not report the endpoint estimate needed to describe the observed outcome in this study.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a Kaplan–Meier estimate represent?

Kaplan–Meier estimation is a general method for summarizing time until an event when participants may have unequal follow-up. A participant whose follow-up ends before progression is observed can still contribute information up to the last known follow-up time. This is called censoring. The method uses the observed event times and the number still under observation at those times to estimate the probability of remaining event-free over time. It does not require every participant to have the same follow-up duration.

For this study, the registry says that Kaplan–Meier estimates and associated 95% confidence intervals would be calculated for progression-free survival at 33 months, separately for Arms 1 and 2. The estimates, confidence intervals, event counts, and details of censoring are not reported in the registry record. Consequently, the planned method can be described, but its numerical results cannot be interpreted.

How should a confidence interval be read?

In general, a confidence interval conveys uncertainty around an estimated quantity. A narrower interval indicates greater precision under the assumptions of the method, while a wider interval indicates less precision. It does not show the range of outcomes for individual participants, and it is not a guarantee that the true value lies within the interval. The 95% confidence intervals named in the registry would quantify uncertainty around the arm-specific Kaplan–Meier estimates. Their bounds are not reported in the registry record, so the precision of those estimates cannot be assessed.

Why do the groups not form a randomized comparison?

Random allocation is intended to make treatment groups comparable, on average, with respect to both measured and unmeasured factors at the start of a study. This trial used non-randomized allocation, with treatment selection linked to tumor molecular characteristics. In general, this creates a risk of confounding: a factor related to both treatment assignment and outcome can make an arm appear to have a different outcome even when the difference is not caused by treatment. Here, tumor features explicitly determined which treatment group applied. The registry also states that the arms are not a like-for-like control comparison. Arm-specific estimates, if available, would therefore describe outcomes within selected groups; they would not by themselves establish a causal treatment effect.

What does intention-to-treat mean in this record?

In general, an intention-to-treat analysis retains participants in the group to which they were assigned or initially allocated, rather than excluding them because they stopped treatment or did not follow the planned treatment course. The registry says that the primary endpoint analysis would use intention to treat and specifically notes that one participant in Arm 2 went off treatment after only a few days but was included in that population. This is a useful statement about inclusion in the planned analysis. It does not specify the participant’s outcome status, the handling of missing outcome information, or whether every other participant had complete follow-up.

What can be inferred from the posted analysis status?

The record lists zero analyses. This does not mean that no analysis was ever performed; it means that no analysis is listed in the registry record. In general, a registered analysis plan helps readers distinguish pre-specified outcomes and methods from analyses chosen after data are examined. The registry describes an intended endpoint method, but a detailed statistical analysis plan, including the approach to missing data, covariate adjustment, or any interim analyses, is not reported in the registry record.

Statistical significance, if reported, would not by itself measure the size or clinical importance of an effect. Likewise, a confidence interval that includes values on both sides of a null or reference value can reflect imprecision as well as absence of a clear difference. No p-value or arm comparison is reported for the primary outcome. Since assignment was non-randomized and the groups were selected by tumor characteristics, a simple statistical comparison would also require careful interpretation even if one were posted.

The record gives no numerical primary outcome estimate, event count, or confidence interval. It also does not report a sample-size justification or a detailed statistical plan. Those omissions prevent assessment of the planned study’s precision, the completeness of endpoint follow-up, and whether the actual analyses followed the intended methods. The registry’s description is sufficient to identify the endpoint framework, but not to assess the trial’s outcome evidence.

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("Arm 1: Everolimus")
n      <- c(16)
events <- c(5)
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  Arm 1: Everolimus  16  5  31.2  11.0  58.7  14.2  55.6  14.2  56.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary progression-free survival outcome and secondary outcomes of median progression-free survival, overall survival rate, objective response rate, and reduction in seizures. Multiple outcomes create a multiplicity issue in general: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses that possibility. The registry record does not report whether any multiplicity adjustment, outcome hierarchy, or other approach to controlling interpretation across outcomes was planned.

The record lists zero analyses, and results for the primary and secondary outcomes are not reported in the registry record. It is therefore not possible to determine which outcomes were analyzed, whether all planned outcomes were reported, or how any multiplicity was handled.

The primary endpoint description states that the analysis would use the intention-to-treat population and includes one Arm 2 participant who stopped treatment after only a few days. Beyond this, the handling of missing outcome data is not reported in the registry record. The record does not specify the amount or pattern of missing follow-up, rules for censoring, or sensitivity analyses for missing data.

Definitions of analysis populations for the secondary outcomes, any per-protocol or safety populations, and the treatment of protocol deviations are not reported in the registry record. These details matter because different analysis populations can produce different summaries, particularly when treatment discontinuation or incomplete follow-up occurs. Without the analysis details and results, the extent to which missingness or selection could affect the reported findings cannot be assessed.

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: headache (11.1%), colitis (11.1%), myalgia (11.1%), cognitive disturbance (11.1%), surgical and medical procedures - other (11.1%).

The registry reports serious adverse-event information separately by treatment group, including the number at risk and the number affected. In Arm 1, 16 participants were listed at risk for serious events and 1 was affected; the corresponding other-event figures were 16 at risk and 12 affected. Two deaths are listed for this arm. In Arm 2, the serious-event figures were 2 at risk and 0 affected; the other-event figures were 2 at risk and 1 affected, with 0 deaths listed. In Arm 3, the serious-event figures were 9 at risk and 3 affected; the other-event figures were 9 at risk and 7 affected, with 0 deaths listed.

These are descriptive counts, not randomized comparisons. The groups differ in size and selection, and the registry does not report whether any event or death was judged related to study treatment. The listed serious-event terms include headache, colitis, myalgia, cognitive disturbance, surgical and medical procedures - Other, and uterine pain; the reported percentages are 11.1% for each of the first five terms and 6.2% for uterine pain. The record does not provide enough detail to infer severity, duration, recurrence, or causality for each term. Counts of events should not be interpreted as proof that a treatment caused or prevented an event.

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

The registry record establishes that a phase II study of everolimus, alone or with temozolomide, was conducted in adults with low-grade glioma using non-randomized, open-label, parallel treatment groups. It describes how molecular tumor features guided treatment assignment and identifies progression-free survival through 33 months as the primary outcome for Arms 1 and 2. It also records selected safety counts and planned secondary outcomes.

It does not provide the primary endpoint estimate, confidence interval, or posted analyses. Therefore, the registry does not establish the observed progression-free survival rate in either arm, the precision of those rates, or whether outcomes differed between arms. It also does not provide results for overall survival, objective response, seizure reduction, or the listed median progression-free survival outcome. No conclusion about treatment benefit or lack of benefit can be drawn from the endpoint information absent from the record.

Even if numerical results were available, the non-randomized design would limit causal interpretation. Assignment depended on tumor characteristics, so differences between groups could reflect those characteristics as well as treatment. The groups should not be read as a treatment-versus-control comparison. The registry gives no reported adjustment strategy that would address this concern.

The safety figures describe events reported within each group but do not establish whether events were caused by treatment. The reason for study termination and the handling of missing outcome information are not reported in the registry record. Overall, the record is informative about the study question, treatment-selection structure, and intended endpoint method, but it is not a report of the outcome evidence needed to judge efficacy or fully characterize safety.

14. Why This Trial Matters Statistically

This study is statistically notable because its treatment groups were defined by tumor biology rather than random allocation. That design raises an important interpretive distinction: an estimate can accurately describe outcomes within a group while still being insufficient to identify the causal effect of treatment. The treatment-selection rules make that distinction especially relevant, because pathway activation and 1p/19q status determined which regimen a participant received.

The primary endpoint also illustrates why time-to-event methods are used. Follow-up can vary, and some participants may not have a recorded progression event by the end of observation. Kaplan–Meier estimation is designed to use available follow-up while accounting for censoring. However, a method alone does not establish the result: without the arm-specific estimates, confidence intervals, and information about follow-up, readers cannot judge either the outcome level or its precision.

The registry’s intention-to-treat note is another useful statistical detail. It identifies a participant who stopped treatment after only a few days but remained in the planned primary analysis population. That clarifies one inclusion decision, while leaving other aspects of missing-data handling unreported.

Finally, the record distinguishes an outcome framework from outcome evidence. It names a primary endpoint, secondary outcomes, and a planned estimation approach, but lists zero analyses and does not report the results. This makes it important to avoid treating a registered question as an answered question. The design information can guide interpretation of any future results, but it cannot substitute for those results.

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 direct limitation is that the registry record does not report the primary progression-free survival estimates or their confidence intervals. Without those results, the endpoint cannot be evaluated for magnitude or precision. Secondary outcome results are also not reported in the registry record, and the record lists zero analyses.

Non-randomized treatment assignment limits comparisons between arms. Assignment was linked to tumor characteristics, so the groups may differ in prognosis or other factors associated with outcome. The record explicitly cautions that the arms are not a like-for-like control comparison. A causal comparison would require suitable design or analytic methods, and such methods are not reported in the registry record.

The study is listed as terminated, but the reason for termination is not reported in the registry record. The recorded enrollment is 27, but the number analyzed for each outcome and the number with complete follow-up are not reported. The record’s note about one Arm 2 participant establishes inclusion in the intention-to-treat population, but does not describe the person’s outcome or the general approach to missing data.

Other details needed to assess the evidence, including baseline characteristics by arm, progression event counts, censoring patterns, a detailed statistical analysis plan, and any sample-size justification, are not reported in the registry record. The arm descriptions are truncated, limiting knowledge of treatment details. Safety information is presented as counts and selected term percentages, without reported attribution to treatment or fuller event-level context. These limitations constrain both efficacy interpretation and the completeness of safety assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Everolimus With and Without Temozolomide in Adult Low Grade Glioma — NCT02023905.
• Registry record last updated 2022-12-29; status last verified 2022-11.
• Results first posted 2022-12-29.
• 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

NCT02023905 is a phase II, parallel-group, non-randomized, unmasked study sponsored by the University of California, San Francisco. Its recorded enrollment was 27, and it is listed as terminated. The study evaluated everolimus alone or with temozolomide in adults with low-grade glioma, with treatment selection based on tumor characteristics including 1p/19q status and PI3K/mTOR pathway activation.

The primary outcome was progression-free survival through 33 months for Arms 1 and 2, planned for assessment using RANO criteria and separate Kaplan–Meier estimates with 95% confidence intervals. The record lists secondary outcomes including median progression-free survival, overall survival rate, objective response rate, and reduction in seizures. Zero analyses are listed, and the primary and secondary outcome results are not reported in the registry record. The reason for termination is also not reported in the registry record.