Magnetic Resonance Spectroscopy Imaging in Predicting Response to Vorinostat and Temozolomide in Patients With Recurrent or Progressive Glioblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Magnetic Resonance Spectroscopy Imaging in Predicting Response to Vorinostat and Temozolomide in Patients With Recurrent or Progressive Glioblastoma (NCT01342757), a na na study. The primary outcome is Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index.

2. Clinical Question

The study’s stated purpose is to examine whether magnetic resonance spectroscopy imaging can help predict response during treatment with vorinostat and temozolomide. That aim involves both measuring a metabolic signal and relating it to treatment response. The registry describes the imaging and the endpoint, but does not report enough participant-level or outcome information to evaluate how well the measurement predicted response.

The question should therefore be read as an exploratory, within-group assessment rather than a comparison of treatment strategies. Without a control group, changes over time cannot be separated from other explanations using this design alone. The record also does not report a response threshold for classifying an individual participant as a responder. Those omissions limit interpretation of the primary question even before considering the absent endpoint result.

3. Trial Design

This was a completed, single-group clinical trial with an enrollment of 12 participants. The registry lists one arm, Arm I, and records allocation as NA and masking as NONE. The phase is also listed as NA. The sponsor is the National Cancer Institute (NCI). The recorded start is 2010-12 and primary completion is 2012-05.

The arm description states that participants received vorinostat once daily on days -7 to -1 during course 1, and on days 8-14 and 22-28; temozolomide was given on days 1-5. Courses were to repeat every 28 days in the absence of disease progression or unacceptable toxicity. Participants also underwent magnetic resonance spectroscopic imaging. The description of the imaging schedule is incomplete in the registry record, so the full schedule cannot be established from it.

The trial’s design does not include a concurrent comparison arm. The single-group structure can describe outcomes among enrolled participants, but it does not provide a randomized contrast that would estimate how outcomes differed under another treatment or no treatment. Allocation is recorded as NA, rather than as a method of assigning participants among groups.

The brief summary describes a population that includes recurrent, progressive, or newly diagnosed glioblastoma, while the title names recurrent or progressive disease. The specific enrolled population and the distribution of disease status among the 12 participants are not reported in the registry record. Likewise, detailed eligibility criteria, the protocol’s rationale for the enrollment target, and any planned interim monitoring are not reported in the registry record.

Although the status is COMPLETED, that status does not itself indicate whether the primary endpoint was met or whether results were statistically conclusive. The registry record lists four outcome measures and identifies a primary endpoint with a 9-week timeframe, but reports no analyses. In particular, no group comparison, adjusted estimate, or inferential result is reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: No events requiring changes in approach or enrollment criteria

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 Proportion of Patients With Magnetic Resonance Spectroscopy (MRS) Response to Initial Vorinostat by MRI and MRS Scans as Determined by Spectroscopic Index, measured over 9 weeks.

The primary endpoint is the proportion of patients with a magnetic resonance spectroscopy response to initial vorinostat, assessed with MRI and MRS scans and determined using a spectroscopic index. Its stated timeframe is 9 weeks. The endpoint is intended to turn changes in several metabolite signals into a measure that can be used to classify response.

The index uses changes in the signals for inositol, choline, lactate, and N-acetylaspartate, normalized to baseline at one and nine weeks. The description says that values for all metabolites at one week are added to form the one-week index, and the calculation is repeated at nine weeks. The index is unitless and has no range limit. Positive values represent normalization of tumor metabolism; negative values suggest no improvement or worsening of metabolic character.

In general, a composite measure can condense multiple signals into one summary, which may make change easier to describe than separate results for every component. But the clinical meaning of a composite depends on how it is constructed and how response is defined. The registry record does not report a cutoff for classifying an individual as a responder, nor does it report the number or proportion classified as having a response. The index’s direction is described, but its relation to a clinically meaningful outcome is not quantified in the registry record.

The primary endpoint title refers to a proportion, which is a binary summary: participants are counted as having or not having the specified response. Without the response rule and observed count, the endpoint cannot be independently interpreted or its precision assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help clarify what the registry record can and cannot establish. In general, statistical methods describe how observations are converted into estimates and how uncertainty is assessed. Here, the endpoint definition is described, but the registry record reports no analyses. The distinction matters: a planned measure is not the same as an observed result, and an observed result is not the same as a comparison that supports a causal conclusion.

What does a proportion summarize?

In general, a proportion is the number of participants meeting a stated condition divided by the number assessed for that condition. For this trial, the condition is an MRS response defined through the spectroscopic index. To interpret a proportion, readers need both the response rule and the number of participants assessed. The registry gives neither a response count nor a denominator for the primary endpoint, and it does not report the response cutoff. Therefore, the primary proportion cannot be reconstructed from the registry record.

For a binary endpoint, an interval estimate can convey how much uncertainty surrounds the estimated proportion. In general, estimates based on small groups tend to be less precise than estimates based on larger groups, although the actual precision depends on the observed data and method. A confidence interval is not a guarantee that the true value lies within a particular interval; it is a method for expressing uncertainty under specified assumptions. No interval estimate for the primary endpoint is reported in the registry record.

What does the index measure?

The registry describes an index based on normalized changes in inositol, choline, lactate, and N-acetylaspartate signals. Values are normalized to baseline at one and nine weeks, and metabolite values are added to create an index at each time. The index is unitless, has no range limit, and has a stated direction of interpretation: positive values represent normalization of tumor metabolism, while negative values suggest no improvement or worsening of metabolic character.

In general, an index that combines several measurements may be useful for reducing a complex set of signals to a single summary. Its interpretation depends on the measurement scale, the calculation, and a rule for linking values to response. If components have different measurement properties, the combination also needs a clear rationale. The registry describes the component signals and broad interpretation, but does not report the response threshold, any validation of that threshold, or the result distribution.

What does a single-group design permit?

In general, a single-group study can describe outcomes observed in its participants. It cannot provide a randomized between-group estimate because there is no separately assigned comparison group. Changes from baseline may be informative descriptively, but they do not isolate the effect of treatment from time trends or other influences. This trial has one listed arm and no like-for-like control comparison. The registry therefore does not support a randomized estimate of treatment effect.

Masking is recorded as NONE. In general, masking can reduce the influence of knowledge about treatment assignment on measurement or assessment, depending on who is masked and how outcomes are obtained. The record does not describe any masking. Because the primary measure involves imaging and signal assessment, details about image acquisition, processing, and assessment would be relevant to interpretation; those details are not reported in the registry record.

How should the planning illustrations be understood?

The registry’s sample-size assumptions describe planning illustrations rather than the trial’s own design justification. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is stated as a fraction of the observed effect. For time-to-event outcomes, the stated planning quantity is a total number of events; for other outcomes, it is participants per arm.

These assumptions do not describe the actual single-group design, which has no two-arm allocation. In general, a sample-size calculation depends on the assumed effect, variability or event rate, significance level, power target, and design. An illustration based on a fraction of an observed effect is conditional on that effect and should not be read as the trial’s original enrollment rationale or as evidence that the trial had a particular probability of finding a result. The observed primary effect is not reported in the registry record, and these planning illustrations are not observed power.

What is absent from the analysis record?

The registry lists four outcome measures, identifies a primary endpoint and a secondary outcome called mean change in metabolite levels, and reports zero analyses. It does not report a statistical model, adjustment variables, a hypothesis test, uncertainty intervals, or an analysis population. In general, those details help readers understand how missing observations, repeated measurements, and multiple outcomes are handled. Their absence means there is no reported inferential analysis to interpret.

Over-dispersion is a general concern when count data vary more than a chosen statistical model expects; accounting for it can affect standard errors and uncertainty intervals. That concept does not establish that over-dispersion applies to this trial. No count model or relevant analysis is reported in the registry record, so no particular variance issue or correction can be attributed to the study.

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 I")
n      <- c(12)
events <- c(0)
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 I  12  0  0.0  0.0  26.5  0.0  24.2  0.2  24.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and identifies one primary endpoint: the proportion of patients with an MRS response at 9 weeks. It also lists mean change in metabolite levels as a secondary outcome. The registry record reports zero analyses, so it does not show which outcomes were analyzed, whether all were reported, or whether any inferential comparisons were made.

In general, testing multiple outcomes or multiple time points can increase the chance of observing an apparently notable result by chance. A statistical analysis plan may address this through a prespecified hierarchy, adjustment, or a clear distinction between confirmatory and exploratory outcomes. Any such multiplicity strategy is not reported in the registry record. It would be inappropriate to assume that an adjustment was or was not used.

The primary endpoint description refers to measurements at one and nine weeks, but the primary timeframe is 9 weeks. The analysis plan for repeated measurements, if any, is not reported in the registry record. The handling of missing scans, incomplete metabolite measurements, and participants who did not reach the endpoint assessment is also not reported. Enrollment of 12 does not establish the number analyzed.

The analysis population is not reported in the registry record. It is therefore unknown whether results, if analyzed, would have included all enrolled participants or a defined subset. The protocol’s handling of withdrawals, protocol deviations, and missing outcome data is not reported in the registry record. These details matter because exclusions or incomplete follow-up can change both the denominator and the interpretation of a response proportion.

These omissions prevent assessment of multiplicity control, missing-data assumptions, and population definitions. They also prevent comparison of planned and reported analyses. The registry record does not establish that any particular approach was used.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypertension (16.7%), thromboembolism (8.3%), thrombocytopenia (8.3%), diarrhea (8.3%), nausea (8.3%).

The registry reports serious adverse events for Arm I among 12 participants at risk: 5 participants were affected. It reports other adverse events among 12 participants at risk: 9 participants were affected. These are separate registry counts; they should not be added to estimate the number of unique participants because the record does not describe overlap between the groups.

The listed serious adverse event terms and percentages are hypertension, 16.7%; thromboembolism, 8.3%; thrombocytopenia, 8.3%; diarrhea, 8.3%; nausea, 8.3%; and vomiting, 8.3%. These figures describe the reported terms, not the number of distinct participants across all terms. A participant may have experienced more than one event, and the registry record does not report participant-level overlap or event counts by severity grade.

In general, adverse-event counts describe what was recorded in a study group; they do not alone establish that treatment caused an event. Interpretation also depends on event definitions, timing, severity, attribution, follow-up, and the number of participants observed. Those details are not reported in the registry record. With no comparator group, the listed counts cannot be contrasted with a concurrent control rate.

The safety information is descriptive and should be read separately from the primary imaging endpoint. It does not establish the study’s response result or resolve the missing efficacy analysis.

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

The record describes a completed study enrolling 12 participants in one treatment arm. Participants received vorinostat and temozolomide and underwent magnetic resonance spectroscopic imaging. The primary endpoint was defined as the proportion with an MRS response to initial vorinostat, determined using a spectroscopic index at 9 weeks. The index uses normalized metabolite signals and has a stated direction of interpretation.

Those design details do not reveal the observed response. The registry record does not report the primary endpoint count, proportion, confidence interval, or statistical analysis. It therefore does not show how many participants met the response definition, how variable the estimate may have been, or whether results were consistent across participants.

The registry’s stated aim concerns using imaging to predict treatment response. But a predictive claim requires information about how imaging results relate to an outcome, including a defined classification rule and an assessment of predictive performance. The record does not report those analyses or a response cutoff. The aim alone is not evidence that prediction was successful or evaluated.

The single-group design also limits comparisons. It can describe results within the group if those results are reported, but it cannot directly estimate how outcomes would differ under another treatment or a control condition. It does not support a randomized treatment-effect comparison. The registry’s safety counts are descriptive and do not fill that gap.

In general, statistical significance and clinical importance are distinct. A result can be estimated precisely but have limited practical importance, or be potentially important but too imprecise to characterize. Neither distinction can be evaluated for the primary endpoint because no result or uncertainty estimate is reported in the registry record. The appropriate conclusion is that the record documents the study question, design, endpoint definition, and some safety counts, while leaving the central efficacy result and its precision unreported.

14. Why This Trial Matters Statistically

This trial is statistically notable for the difference between its stated aim and the information available for evaluating that aim. The registry describes an imaging measure intended to predict response, yet it reports no primary endpoint result or analysis linking the imaging measure to an outcome. This makes it a useful example of why a well-defined measurement plan and a completed study status are not substitutes for posted results.

The single-group design is important to interpretation. Such a design can support descriptive assessment within the treated group, but it cannot supply a randomized comparison against another treatment. The absence of a comparator also limits how confidently observed changes, if reported, could be attributed to the treatment regimen rather than other influences.

The endpoint combines multiple metabolite signals into a unitless index, then frames the primary outcome as a responder proportion. That path from measurements to a binary response depends on a clearly defined rule. The record describes the index’s components and direction but does not report the classification threshold or the observed response count. This illustrates how an endpoint can be named without enough information to reproduce its clinical classification.

The enrollment of 12 participants makes transparent reporting of denominators, missing assessments, and uncertainty especially relevant. The record does not report the number assessed at the primary time point, an estimate’s precision, or the analysis population. The statistical interpretation therefore cannot proceed from enrollment alone.

Finally, planning illustrations must be separated from actual trial design and outcome evidence. Their stated assumptions describe hypothetical two-arm calculations, whereas the registered study has one arm. They are not observed power and do not establish that the study was designed around a particular effect. The record is most informative as a description of the intended design and endpoint, not as evidence about the magnitude or reliability of the primary response.

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 central limitation is that the registry record does not report the primary endpoint result or any analyses. It therefore gives no observed response proportion, uncertainty estimate, or test result. The number of participants who completed the 9-week assessment is also not reported, so the endpoint denominator cannot be established from enrollment alone.

The response classification rule is not reported. Although the spectroscopic index’s component metabolites and direction are described, the record does not state the cutoff used to classify a participant as a responder. Without that rule, the primary endpoint cannot be independently reconstructed from the index description.

The study has one listed arm and no concurrent comparator. As a result, it cannot provide a randomized comparison of treatment strategies. The registry also does not report how imaging measurements were acquired, processed, or assessed, or whether those assessments were masked. The masking field is NONE.

The brief summary refers to recurrent, progressive, or newly diagnosed glioblastoma, while the title refers to recurrent or progressive disease. The specific enrolled disease-status composition and detailed eligibility criteria are not reported in the registry record. The arm’s imaging schedule is incomplete in its description, and analysis populations, missing-data procedures, and the statistical plan are not reported.

The safety counts are limited by the lack of reported detail on event timing, grades, attribution, and overlap among terms. The record’s completion status does not resolve these limitations or supply an efficacy result. Together, these gaps restrict reproducibility and prevent assessment of the primary endpoint’s magnitude, precision, and predictive performance.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Magnetic Resonance Spectroscopy Imaging in Predicting Response to Vorinostat and Temozolomide in Patients With Recurrent or Progressive Glioblastoma — NCT01342757.
• Registry record last updated 2018-01-29; status last verified 2018-01.
• Results first posted 2014-06-11.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes a completed, single-group study sponsored by the National Cancer Institute (NCI), with an enrollment of 12. The recorded start is 2010-12 and primary completion is 2012-05. Phase and allocation are listed as NA, masking as NONE, and one arm is described.

The study combined vorinostat, temozolomide, and magnetic resonance spectroscopic imaging. Its primary endpoint was the proportion of patients with an MRS response to initial vorinostat, assessed by MRI and MRS using a spectroscopic index at 9 weeks. The index description covers normalized inositol, choline, lactate, and N-acetylaspartate signals.

The registry lists four outcome measures and reports zero analyses. It does not report the primary endpoint result, an analysis population, missing-data procedures, or a statistical analysis plan. Serious adverse events affected 5 of 12 participants at risk, and other adverse events affected 9 of 12 participants at risk. The record supports a description of the design and endpoint, but not an estimate of primary response or its precision.