Valproic Acid in Treating Patients With Progressive, Non-Metastatic Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Valproic Acid in Treating Patients With Progressive, Non-Metastatic Prostate Cancer (NCT00670046), a randomized phase 2 study. The primary outcome is Number of Participants Exhibiting an Increase in Observed or Predicted Prostate-specific Antigen (PSA) Doubling Time.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group phase II study sponsored by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The registry lists an enrollment of 15 and identifies the condition as prostate cancer. The study started in 2008-05, had a primary completion date of 2012-07, and is recorded as terminated. The reason for termination is not reported in the registry record.

Participants were assigned to standard-of-care observation or valproic acid. The valproic acid regimen was oral administration twice daily for up to 1 year, subject to disease progression or unacceptable toxicity. The observation arm followed standard of care. Both arms were scheduled to complete quality-of-life questionnaires at baseline, 6 months, and 1 year. The record does not describe a masking procedure; its design information indicates that the study was unmasked.

The primary outcome was a count of participants with an increase in observed or predicted PSA doubling time. PSA was measured monthly during the study period, and PSA doubling time was calculated. The outcome description also defines any increase in PSA doubling time as a partial response and a doubling time > 10 month as a complete response; those response categories are listed among the secondary outcomes. Other listed outcomes include duration of PSA response as assessed by PSA doubling time and the Functional Assessment of Cancer Therapy - Prostate score.

The posted primary outcome counts are 3 in the standard-of-care arm and 5 in the valproic acid arm, with 6 participants listed in each arm for that outcome. The registry also notes that one participant in Arm I was lost to follow-up and that one participant in Arm II was lost to follow-up while another withdrew consent. The record does not explain how those participants were handled in the outcome analysis or give a reason for the study’s termination.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One participant from Arm 1 was lost to follow-up; One participant from Arm II was lost to follow-up and another withdrew consent

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Exhibiting an Increase in Observed or Predicted Prostate-specific Antigen (PSA) Doubling Time, measured over 1 year.

The primary endpoint counts participants whose observed or predicted PSA doubling time increased after study initiation. PSA doubling time is a measure based on the rate at which PSA levels rise over time. In general, a longer doubling time means PSA is increasing more slowly; a change in that time can therefore be used as a marker of the biochemical course of disease. This endpoint is a laboratory-based measure, not a direct measure of symptoms, survival, or quality of life.

According to the registry, blood was drawn monthly during the 1-year study period, serum PSA was measured, and PSA doubling time was calculated. The endpoint description defines any increase in PSA doubling time as a partial response. It separately identifies a doubling time > 10 month as the complete-response criterion, referring to the cited basis in the registry description. These categories are related but are not identical: the primary outcome is the number exhibiting an increase, while complete and partial response are listed as secondary outcomes.

A count is easy to interpret as the number of participants meeting a criterion, but it does not by itself describe the proportion of all assigned participants who met it or the uncertainty around an arm-to-arm contrast. The posted primary outcome gives 3 participants for standard of care and 5 for valproic acid, with 6 listed in each arm. No confidence interval or inferential test for the primary endpoint is reported in the registry record. The registry also does not provide enough detail to assess the precision of individual PSA doubling-time estimates or the rules used to calculate them when measurements were missing.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods determine how observations are converted into estimates and how uncertainty is assessed. The registry identifies this as a randomized, parallel-group phase II study with no masking. It does not report a statistical analysis plan, a primary hypothesis test, or an analysis population. The descriptions below explain relevant concepts generally; they should not be read as methods confirmed for this study unless explicitly stated in the registry record.

What does the primary outcome count?

The primary measure is a count of participants exhibiting an increase in observed or predicted PSA doubling time. Each participant is classified according to whether the stated criterion was met. In general, such an outcome is binary at the participant level—criterion met or not met—even though the reported summary is a count of participants meeting it. Counts are descriptive. To compare arms inferentially, an analysis would ordinarily specify how to account for the number of participants assessed in each arm, define the effect measure of interest, and quantify uncertainty.

The record reports 3 participants in the standard-of-care arm and 5 in the valproic acid arm, with 6 participants listed per arm for the endpoint. It does not report a test or an estimated contrast. No unadjusted recalculation is reported as an alternative result, and no sponsor analysis of the comparison is posted. Accordingly, there is no inferential result to interpret alongside the raw counts.

Why does randomization matter?

In general, random assignment is intended to make the treatment groups comparable with respect to measured and unmeasured factors, on average. It helps support a causal interpretation of an arm comparison when allocation is implemented as planned, follow-up is adequate, and the analysis respects the randomization. Randomization does not guarantee balance in every small study, nor does it compensate for missing outcome data or an unclear analysis population. The registry identifies the allocation as randomized but does not report the randomization sequence method, concealment procedure, or details about adherence to the assigned intervention.

The study was unmasked. In general, lack of masking can affect behavior, follow-up, co-interventions, or assessment, depending on the outcome and procedures. PSA is a laboratory measure, but the registry does not describe safeguards for measurement or calculation, nor does it report whether outcome assessment was blinded. It would be inappropriate to assume either that masking was used or that lack of masking caused bias.

What would a confidence interval add?

General explanation: an estimate summarizes the observed data, while a confidence interval communicates uncertainty under a statistical model. For a binary endpoint, an interval could accompany an arm-specific proportion or a contrast between arms. Its width depends on the amount of information, the observed data, and the method used. With sparse data, estimates can be imprecise, and some standard approximations may perform poorly. The registry record gives no confidence interval for the primary endpoint, so the precision of any arm contrast cannot be read from the posted counts alone.

A p-value would answer a different, narrower question: under a stated null hypothesis and model, how compatible are the observed data with that hypothesis? It would not show the probability that the null hypothesis is true, establish clinical importance, or replace an effect estimate and confidence interval. No p-value or primary endpoint test is reported in the registry record.

How should planning calculations be understood?

General explanation: sample-size planning uses assumptions about the effect a future study is intended to detect, the statistical test, allocation, and acceptable error rates. The registry’s planning assumptions describe a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the current study had a particular probability of detecting an effect. The registry record does not report the trial’s own sample-size justification. No planning estimate should be interpreted as a result observed among participants.

Planning from an observed effect can be especially unstable when the original study is small, because the observed effect may be imprecise. A planning illustration based on a fraction of that observed effect explores a scenario; it does not establish that the scenario is clinically meaningful or that the assumptions will hold in another study. The registry’s stated planning assumptions do not substitute for a prespecified statistical plan or a reported analysis of the primary outcome.

Why are response categories and repeated measures relevant?

The primary endpoint is based on PSA doubling time, which itself is calculated from PSA measurements over time. Repeated measurements can help characterize a trajectory, but the calculation can depend on the timing and availability of measurements and on the method used to estimate the trajectory. The record says blood was drawn monthly and PSA doubling time calculated, but it does not detail the calculation method, minimum measurement requirements, or handling of missing measurements. Those details are important for reproducing the endpoint.

The record defines any increase in PSA doubling time as partial response and a doubling time > 10 month as complete response. In general, turning a continuous measure into categories can make a result easier to communicate, but it discards information about the amount of change and makes the result sensitive to the chosen threshold. The registry lists complete and partial responses as secondary outcomes; it does not report their counts in the registry record for the primary endpoint. These response definitions should not be conflated with a statistical test of the primary endpoint.

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 (Standard of Care)", "Arm II (Valproic Acid)")
n      <- c(6, 6)
events <- c(3, 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 I (Standard of Care)  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6
ARM  Arm II (Valproic Acid)  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures: the primary PSA doubling-time increase outcome and secondary measures that include duration of PSA response, complete response, partial response, and the Functional Assessment of Cancer Therapy - Prostate score. Considering multiple outcomes can raise the general statistical issue of multiplicity: the more hypotheses tested, the greater the chance that at least one result appears notable by chance if no adjustment or interpretation plan is used. The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified strategy for interpreting multiple tests. It also reports no analyses, so there are no posted test results to assess for multiplicity.

The primary outcome description records follow-up losses: one participant in Arm I was lost to follow-up; one participant in Arm II was lost to follow-up and another withdrew consent. This information matters because outcome availability can affect the estimate and its interpretation. The registry record does not specify whether these participants were included in an analysis, how missing PSA measurements were handled, or whether any imputation or sensitivity analysis was performed. The number listed for the primary endpoint in each arm does not establish which analysis population was used.

In general, an intention-to-treat analysis retains participants in the groups to which they were randomized, while a complete-case analysis uses participants with observed outcomes. Those approaches answer questions under different assumptions, and neither can be attributed to this trial from the registry information. The record also does not report a protocol-defined approach to withdrawals, a missing-data assumption, or an analysis of the quality-of-life outcomes. These omissions limit assessment of whether missingness or multiple outcomes influenced the reported findings.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry reports no serious adverse events and no other adverse events in either arm. It lists 7 participants at risk for serious adverse events and 7 at risk for other adverse events in the standard-of-care arm; for the valproic acid arm, it lists 8 at risk for each category. No deaths are listed in either arm. These are the posted safety figures, and they should be read as registry counts rather than as evidence that risk was absent.

General statistical context: a count of zero observed events does not prove that an event cannot occur. The frequency and precision of a safety estimate depend on the amount of follow-up and the number of participants observed, as well as on how events were defined and collected. The registry information does not provide event descriptions, exposure time, severity breakdowns beyond the serious/non-serious distinction, or a statistical comparison between arms. The serious-event term list is empty.

The primary outcome lists 6 participants per arm, while the safety record lists different numbers at risk. The record does not explain the relationship between those populations. These figures should therefore not be combined or used to infer why the safety and efficacy counts differ. In particular, the absence of recorded events in this small study does not establish comparative safety.

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

The result means that, among the participants represented in the posted primary outcome, 3 in the standard-of-care arm and 5 in the valproic acid arm were recorded as exhibiting an increase in observed or predicted PSA doubling time. The registry lists 6 participants in each arm for that endpoint. PSA was measured monthly during the 1-year study period, according to the outcome description. These statements describe the registry’s recorded findings; they do not establish the size, precision, or cause of an arm difference.

The result does not establish that valproic acid changes PSA doubling time, that any change is clinically meaningful, or that an observed change would persist. The registry reports no inferential comparison, confidence interval, or p-value for the primary endpoint. It also does not explain how the reported counts relate to the noted losses to follow-up and withdrawal. Without those details, the counts cannot be treated as a complete account of outcomes among everyone enrolled or assigned.

The endpoint is a PSA-based measure, not a direct report of symptoms, survival, or quality of life. Although quality of life and other response measures are listed, corresponding results are not reported in the registry record for this account. The record’s rationale describes a possible biological basis for valproic acid, but the posted outcome counts do not test that mechanism. Nor does the study status of terminated explain why the study ended; the reason is not reported in the registry record.

In general, a randomized study can provide evidence about a treatment comparison when its allocation, follow-up, outcome definitions, and analysis are sufficiently described. Here, randomization is recorded, but important analytic details and an inferential result are absent. The appropriate reading is therefore descriptive and cautious: the registry documents these counts in this study, but they do not settle the comparative question or establish how results would apply beyond the participants studied.

14. Why This Trial Matters Statistically

This trial illustrates the difference between reporting an outcome count and reporting a statistical comparison. The registry records a randomized design and gives counts for participants with an increase in PSA doubling time, but it does not provide a test, effect estimate, or uncertainty interval. A reader can identify what was counted without being able to assess the precision of a contrast or how compatible it is with chance variation.

The study also highlights the importance of aligning the outcome definition, analysis population, and missing-data account. PSA doubling time is calculated from repeated PSA measurements, while the registry notes lost follow-up and withdrawal. Without the calculation details and an explanation of how missing observations were handled, reproducibility and interpretation are limited. The outcome counts alone cannot resolve those issues.

The small number of participants listed per arm for the primary outcome also makes clear why descriptive counts should not be mistaken for stable estimates. In general, sparse data can yield substantial uncertainty, even when the counts appear straightforward. A completed randomized comparison is not automatically an informative inferential analysis: readers also need a clear statistical plan, suitable methods, and measures of uncertainty.

Finally, the record lists multiple outcomes and reports no analyses. This makes multiplicity and selective emphasis difficult to evaluate. Statistical interpretation depends not only on the numerical result but also on knowing which outcomes were prespecified, how they were analyzed, and what was missing. These are general lessons for reading clinical trial records, especially when they contain descriptive findings without a reported analysis.

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 primary outcome is reported as counts, without a statistical comparison, confidence interval, or p-value. The registry’s analysis information reports no analyses, and it does not provide an analysis plan or define the population used for the endpoint. This prevents assessment of the precision of the arm contrast and the assumptions behind any inferential claim.

There are also unresolved questions about outcome availability. The primary outcome description notes one participant lost to follow-up in Arm I and one lost to follow-up plus one withdrawal of consent in Arm II. The record does not say how those participants were treated in the analysis or how missing PSA measurements were handled. Although it describes monthly blood draws and PSA doubling-time calculation, it does not specify the calculation method or its requirements for available measurements.

The registry’s enrollment is 15, while 6 participants are listed in each arm for the primary outcome; the record does not explain the relationship between these figures. The safety fields list different numbers at risk, and the record does not describe how those populations relate to the endpoint population. These figures should not be reconciled by assumption.

The study is listed as terminated, but the reason is not reported in the registry record. The record also does not provide detailed eligibility criteria, randomization procedures, adherence information, or the outcomes of the listed secondary measures. These missing details constrain evaluation of trial conduct, generalizability, and the completeness of the reported results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Valproic Acid in Treating Patients With Progressive, Non-Metastatic Prostate Cancer — NCT00670046.
• Registry record last updated 2018-09-28; status last verified 2018-09.
• Results first posted 2018-09-28.
• 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

This randomized, unmasked, parallel-group phase II study compared standard-of-care observation with oral valproic acid in patients described as having progressive, non-metastatic prostate cancer. Valproic acid was given twice daily for up to 1 year unless progression or unacceptable toxicity occurred. The registry lists enrollment of 15, a start date of 2008-05, primary completion in 2012-07, and status as terminated.

The primary outcome was the number of participants exhibiting an increase in observed or predicted PSA doubling time during the 1-year study period. The registry reports 3 participants in the standard-of-care arm and 5 in the valproic acid arm, with 6 listed in each arm. It reports no analyses or inferential comparison. The record notes follow-up losses and a withdrawal, but does not describe how missing data were handled. It reports zero serious adverse events, zero other adverse events, and zero deaths in both arms; the reason for termination is not reported in the registry record.