A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide (NCT01977651), a na phase 4 study. The primary outcome is The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC).

2. Clinical Question

This question is focused on the occurrence of a confirmed seizure during an explicitly bounded treatment period. It is not a comparison of seizure risk against an untreated group or another therapy. The study objective was to evaluate seizure incidence and monitor safety in mCRPC participants known to have seizure risk factor(s). The endpoint depends on the SRES definition, which includes participants who had a confirmed seizure during the treatment period or who completed at least 3 months (75 percent [%]) of planned treatment. That definition is relevant when interpreting any percentage: its denominator is not automatically the enrollment figure. The registry record does not report the endpoint numerator, the number of participants in the SRES, or the percentage with a confirmed seizure.

3. Trial Design

The registry describes a Phase 4, multicenter, single-arm, open-label, postmarketing safety study. Its listed allocation is NA, masking is NONE, and model is SINGLE GROUP. These features indicate that the study was not a randomized treatment comparison and that no masking was listed. The enrollment figure is 424. The condition under study was metastatic castration-resistant prostate cancer (mCRPC), and the intervention was enzalutamide.

Participants received enzalutamide 160 mg orally once a day for 4 months. At the end of the 4-month treatment period, participants assessed as deriving benefit continued into an extension period. The duration of study drug treatment in the extension is not reported in the registry record. The study started on 2013-09-25, had primary completion on 2016-02-01, and is listed as COMPLETED.

The primary outcome concerned the percentage of evaluable participants with at least one confirmed seizure adjudicated by the IAC during Day 1 up to week 17. The SRES included participants with a confirmed seizure during the 4-month treatment period or participants who completed at least 3 months (75 percent [%]) of planned treatment. This is an endpoint-specific population definition. It should not be treated as interchangeable with the enrollment figure or with the adverse-event group’s listed at-risk count.

No control group is described, so the design can describe events observed during treatment but cannot estimate a randomized between-group treatment contrast. The registry record lists one outcome measure and no analyses. It does not report the study’s detailed statistical analysis plan, a sample-size justification, or an interim-analysis plan. Those items should not be inferred from the study’s Phase 4 status or its safety objective.

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: Participants who met all inclusion and none of the exclusion criteria were enrolled in the study, completing a 4-month treatment period. Participants who benefited from the treatment were allowed to continue in the extension period. A total 424 participants were enrolled and 423 participants received the study drug.

4 Month Treatment Period

Reasons for not completing this period:

1 Year Extension Period

Reasons for not completing this period:

Post 1 Year Extension Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The seizure risk evaluation set (SRES) consisted of all participants with a confirmed seizure during the 4-month treatment period of the study or who completed at least 3 months (75 percent \[%\]) of the planned treatment.

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.

Population: The safety analysis set (SAF) consisted of all participants who took at least 1 dose of study drug and for whom any data was reported after first dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC), measured over Day 1 up to week 17 (end of 4-month treatment period).

The primary endpoint is the percentage of evaluable participants with at least one confirmed seizure adjudicated by the Independent Adjudication Committee (IAC). Its timeframe is Day 1 up to week 17, the end of the 4-month treatment period. The SRES definition includes participants with a confirmed seizure in that period or participants who completed at least 3 months (75 percent [%]) of planned treatment.

A percentage is a way to express how often a defined event occurred within a defined population and observation period. In this case, the event is at least one confirmed seizure, rather than every seizure episode. Independent adjudication is part of the endpoint definition: the endpoint is based on seizures confirmed by the IAC, not simply on an unspecified report of a possible event. The registry record does not provide further detail about adjudication procedures.

This endpoint is used to describe seizure occurrence during the specified treatment period in a population selected for seizure risk factors. Its interpretation depends on knowing both the number meeting the endpoint and the number included in the SRES. Neither the primary percentage nor its 95% confidence interval is reported in the registry record. The endpoint therefore cannot be quantified from the registry entry, and the enrollment figure should not be substituted for the endpoint denominator.

As a general statistical point, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the method used. The registry identifies a 95% confidence interval as the dispersion measure for this outcome, but the interval itself and the method used to calculate it are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a binary percentage endpoint: whether an evaluable participant had at least one confirmed seizure during the specified treatment period. It also lists a 95% confidence interval as the dispersion measure. However, it does not report the endpoint estimate, its confidence limits, or the calculation method. The distinctions below explain how such an endpoint is generally interpreted without attributing unreported methods to this study.

What does a percentage endpoint represent?

For a binary endpoint, each participant is classified according to whether the specified event occurred within the defined period. The estimated percentage describes the proportion meeting the event definition within the analysis population. Here, the event is at least one confirmed seizure adjudicated by the IAC, and the period is Day 1 up to week 17. This is a participant-level endpoint: the definition concerns whether a participant had at least one event, not the total number of seizure episodes.

The denominator matters as much as the event count. The primary population is the SRES, defined as participants with a confirmed seizure during the 4-month treatment period or participants who completed at least 3 months (75 percent [%]) of planned treatment. The record does not state the number included in that set. It also does not state whether any participants were excluded from the endpoint calculation for other reasons. The enrollment figure is a separate study characteristic and should not be treated as the endpoint denominator without evidence that the populations coincide.

What does the confidence interval add?

In general, a confidence interval conveys statistical uncertainty around an estimate. A narrower interval indicates greater precision under the assumptions of the method; a wider interval indicates less precision. An interval is not a guarantee that the underlying value lies within its limits, and it does not describe the range of outcomes for individual participants. The registry identifies a 95% confidence interval for this endpoint, but neither its limits nor the method used to calculate it are reported in the registry record.

For a binary percentage, possible methods include procedures based on different assumptions about the distribution of the estimate. Those methods can behave differently, particularly when event counts are sparse or when estimates are near the boundaries of the possible range. The registry does not identify which procedure was used, so it would be inappropriate to assign a specific method or to recalculate an interval from information that is not reported.

How does adjudication relate to the endpoint?

The endpoint specifies that seizures must be confirmed by the IAC. Adjudication is a way of applying an endpoint definition to reported events; the resulting classification determines whether an event meets the endpoint. The record does not describe the committee’s criteria, its review process, or how disagreements were handled. These details should not be inferred from the fact that independent adjudication was used.

The endpoint is limited to at least one confirmed seizure within its stated period. It does not, by its definition alone, convey the timing of an event, the number of episodes after the first, or the duration of follow-up beyond that period. The registry does not report time-to-event analyses for this primary outcome. Thus, the listed endpoint should be read as a period-specific percentage rather than as a rate per unit of time or a survival estimate.

What can be inferred from the study structure?

The study is listed as single-group, open-label, and nonrandomized, with no comparator arm. A single-group percentage can describe the observed outcome in the study population. It cannot by itself identify what would have happened to comparable participants under a different treatment or without treatment. This is a general limitation of noncomparative designs, not evidence that the endpoint was measured incorrectly.

The registry lists one outcome measure and zero analyses. No detailed statistical analysis plan, missing-data method, subgroup plan, or interim-analysis plan is reported in the registry record. The absence of those details in the entry does not prove that no such work occurred; it means the entry does not document it. Results should not be reverse-engineered from the study objective or from other safety summaries.

How should planning illustrations be read?

The record describes planning illustrations as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not a description of the actual single-group design. The registry does not report numerical planning results or the primary observed effect needed to interpret such illustrations.

As a general point, a sample-size illustration answers a hypothetical planning question under its assumptions. It is not the number of participants observed in a trial and is not observed power. In this case, a two-arm illustration should not be mistaken for evidence that this study had a comparator arm: the trial itself is listed as single-group. The registry record also does not report a sample-size justification for the study’s own design.

Over-dispersion is a general concern when observed variability exceeds what a simple statistical model assumes. It can affect uncertainty estimates and the suitability of a model. The registry does not report a model for the primary percentage or evidence of over-dispersion, so no study-specific claim about it is warranted. More broadly, the endpoint estimate, denominator, confidence interval, and analysis details would be needed to assess precision and the sensitivity of conclusions to modeling choices.

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("Enzalutamide 160 mg")
n      <- c(366)
events <- c(4)
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  Enzalutamide 160 mg  366  4  1.1  0.3  2.8  0.4  2.8  0.4  2.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and zero analyses. The primary endpoint is the percentage of evaluable participants with at least one confirmed seizure adjudicated by the IAC during Day 1 up to week 17. Although the record identifies this endpoint and a 95% confidence interval as its dispersion measure, the estimate and interval are not reported in the registry record.

Multiplicity concerns arise when several outcomes, time points, comparisons, or subgroup analyses are tested or interpreted together. Such choices can affect how statistical evidence is understood. The registry record does not report a multiplicity adjustment, a testing hierarchy, or a broader statistical analysis plan. The listed number of outcome measures alone does not establish which analyses were planned or whether any adjustments were considered. No unreported testing strategy should be assumed.

The endpoint population is the SRES: participants with a confirmed seizure during the 4-month treatment period or participants who completed at least 3 months (75 percent [%]) of planned treatment. The size of that population is not reported. The record does not state how missing endpoint information was handled, whether any data were imputed, or how participants who did not meet the SRES definition were treated in analyses. The population definition should therefore be kept distinct from assumptions about missing-data handling.

In general, missing-data methods matter because conclusions can depend on why information is unavailable and on how the analysis treats participants without a complete endpoint assessment. The registry record does not report the reasons for missing information or an analysis addressing its potential effect. It also does not report sensitivity analyses for alternative population definitions or missing-data assumptions. These are limitations of the information recorded; they do not establish that missing data occurred or that a particular method was used.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: malignant neoplasm progression (8.0%), pneumonia (3.1%), general physical health deterioration (2.4%), fall (2.4%), confusional state (2.4%).

The safety listing gives an at-risk count of 423 for serious adverse events and an affected count of 193. For other adverse events, the at-risk count is 423 and the affected count is 318. The registry also lists 62 deaths. These are safety summaries, separate from the primary seizure endpoint. The counts should be read as the registry records them, without calculating additional percentages or combining categories.

The listed serious adverse-event terms and percentages are malignant neoplasm progression, 8.0%; pneumonia, 3.1%; general physical health deterioration, 2.4%; fall, 2.4%; confusional state, 2.4%; and anaemia, 2.1%. These entries describe the terms and percentages recorded for serious events. They do not provide the primary endpoint result, and the record does not establish from these figures alone whether an event was caused by treatment.

Counts for different adverse-event groupings should not be added to create a total number of affected participants. A participant may contribute to more than one event category, and the record does not describe overlap across categories. The death count also should not be interpreted as treatment-related mortality: the listed count alone does not establish cause or attribution. Further detail about event definitions, seriousness criteria, follow-up, and attribution is not reported in the registry record.

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

The registry record describes a study designed to monitor safety and evaluate seizure incidence among mCRPC participants known to have seizure risk factor(s) who received enzalutamide. It specifies a primary endpoint based on at least one confirmed seizure adjudicated by the IAC during Day 1 up to week 17. It does not report the primary endpoint’s event count, analysis population size, percentage, or 95% confidence interval. As a result, the record does not show the observed seizure percentage or how precisely it was estimated.

The study’s single-group design supports description of safety outcomes in the enrolled study population, but it does not provide a randomized comparison with another treatment or an untreated group. Without a comparator, the endpoint cannot by itself separate outcomes associated with treatment from outcomes that might also occur because of participants’ underlying condition, seizure risk factors, or other circumstances. This is a general interpretive limitation of the design, not a claim about the cause of any individual event.

The endpoint population is defined by the SRES criteria, not simply by enrollment. The record does not report the SRES size or explain how missing endpoint information was handled. Therefore, the enrollment figure cannot be used to infer the primary percentage or its precision. The listed serious and other adverse-event counts provide separate safety information, but they do not fill the gap in the primary seizure result.

The record also does not report the detailed statistical analysis plan, any multiplicity approach, or interim analyses. It lists zero analyses, which describes the registry entry rather than establishing what analyses were conducted elsewhere. Any stronger claim about the study’s statistical findings, causal effects, or generalizability would require information beyond what the registry record reports. The appropriate reading is therefore limited: the study question and design are documented, while the principal seizure estimate and several key analysis details are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable because its primary question concerns a defined safety event in a population selected for seizure risk factors. The endpoint is not simply any reported neurological event: it is at least one confirmed seizure adjudicated by the IAC, within a specified treatment period. Clear event definitions and observation windows are central to interpreting safety estimates, because changing either can change what the percentage represents.

The SRES definition also makes the analysis population especially important. It includes participants with a confirmed seizure during the 4-month treatment period or participants who completed at least 3 months (75 percent [%]) of planned treatment. Since the registry does not report the size of that set or the endpoint estimate, readers cannot verify the denominator or judge the precision of the primary finding from this entry. This illustrates why an enrollment figure and a result denominator are not interchangeable.

The single-group design frames what the study can answer. It can describe the recorded safety experience in its study population, but it cannot produce a randomized comparison with a control group. This distinction matters when interpreting event counts: observation during treatment is not, on its own, an estimate of the difference attributable to treatment.

The record also illustrates the difference between a defined endpoint and a reported result. It identifies a 95% confidence interval as the measure of dispersion, yet does not report the endpoint estimate or interval. Without those values, neither the magnitude of the observed percentage nor its statistical precision can be evaluated. The listed adverse-event summaries remain useful as separate registry information, but they do not replace the missing primary seizure result or establish causation.

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 of the registry entry is that it does not report the primary endpoint result. The number of evaluable participants, the number with at least one confirmed seizure, the resulting percentage, and the 95% confidence interval are not reported in the registry record. This prevents assessment of the observed seizure frequency and its precision.

The primary population is defined by the SRES criteria, but its size is not reported. The record does not explain how missing endpoint information was handled, whether endpoint assessments were incomplete, or whether sensitivity analyses were conducted. It also does not report the method used to calculate the confidence interval or provide details of the IAC adjudication process.

The study is single-group and open-label, with no comparator listed. Consequently, the design does not support a randomized between-group estimate. The registry record does not report a detailed statistical analysis plan, a multiplicity strategy, an interim-analysis plan, or a sample-size justification for the study’s own design. These omissions limit what can be concluded about planned statistical procedures, but should not be read as proof that a procedure was or was not used outside the registry entry.

The extension period introduces another boundary in the available description: participants assessed as deriving benefit continued after the 4-month treatment period, but the duration of study drug treatment in that extension is not reported in the registry record. The primary seizure endpoint, however, is specified through week 17. The record does not provide enough detail to characterize longer-term seizure follow-up. Finally, serious and other adverse-event summaries are listed, but the information does not establish event attribution or provide the missing primary seizure estimate.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide — NCT01977651.
• Registry record last updated 2024-12-06; status last verified 2024-11.
• Results first posted 2020-12-09.
• 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 Phase 4, multicenter, single-arm, open-label, postmarketing safety study of enzalutamide in participants with metastatic castration-resistant prostate cancer known to have seizure risk factor(s). Enrollment is listed as 424. Participants received enzalutamide 160 mg orally once a day for 4 months; participants assessed as deriving benefit could continue into an extension period, whose total treatment duration is not reported in the registry record.

The primary endpoint was the percentage of evaluable participants with at least one confirmed seizure adjudicated by the IAC from Day 1 up to week 17. The endpoint population was the SRES, as defined by seizure occurrence or treatment completion criteria. The registry lists one outcome measure and zero analyses, but does not report the primary endpoint result or its 95% confidence interval. Serious and other adverse-event counts, selected serious-event terms, and a death count are recorded separately. The study has no comparator group, and the registry entry does not report a detailed statistical analysis plan, missing-data methods, or multiplicity procedures.