Observational Study for the Evaluation of Long-term Safety of Radium-223 Used for the Treatment of Metastatic Castration Resistant Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Observational Study for the Evaluation of Long-term Safety of Radium-223 Used for the Treatment of Metastatic Castration Resistant Prostate Cancer (NCT02141438), a registered phase not stated study. The primary outcome is Number of Participants With Second Primary Malignancies (SPM).

2. Clinical Question

The study’s stated purpose was to evaluate the short- and long-term safety profile of Radium-223 in routine clinical practice and to evaluate the risk of second primary cancers. Its primary outcome concerns the count of participants with second primary malignancies, rather than a comparison of treatment effects between groups.

The outcome timeframe begins at initiation of Radium-223 and covers the treatment period, described as up to 6 months and including 6 cycles every 4 weeks, through 7 years after the last dose. The registry record does not report the observed primary-outcome count or a corresponding estimate of risk. It also does not report a comparison group against which that risk could be contrasted.

Other listed outcomes include overall survival, pain scores and pain interference measured using the Brief Pain Inventory Short Form, bone fractures, and bone-associated events. Their presence as planned or listed outcomes does not establish what was observed: results for these outcomes are not reported in the registry record.

3. Trial Design

This is an observational study in routine clinical practice, not a randomized controlled trial. The registry describes a single-arm cohort of people with castration-resistant prostate cancer and bone metastases who were treated with Radium-223 dichloride. It identifies no comparator cohort. Allocation is not stated, and the registry cautions that any arms are not a like-for-like control comparison.

The record reports enrollment of 1472. That is the enrollment figure, not necessarily the number contributing data to every outcome or follow-up time. The primary outcome specifies the safety analysis set, but the registry record does not describe how that set was defined or how many participants contributed to each outcome analysis.

The study began on 2014-08-20, reached primary completion on 2024-08-02, and is listed as completed. These registry dates describe the study record; they do not establish that every participant was observed for the full outcome timeframe. The planned primary-outcome timeframe extends from initiation of Radium-223, through a treatment period up to 6 months, and up to 7 years after the last dose.

Because treatment occurred in routine practice and the study has no randomized control group, the design is suited to describing observed events in the enrolled cohort, subject to the completeness and duration of follow-up. It cannot by itself isolate the effect of Radium-223 from underlying disease, other care, participant characteristics, or other factors that may influence outcomes. The registry record does not report an adjusted comparative analysis.

The record lists 13 outcome measures and no analyses. It does not report the study’s statistical analysis plan, sample-size justification, interim analyses, or the methods used to handle incomplete follow-up. Those omissions limit the conclusions that can be drawn about how outcomes were selected, analyzed, and interpreted.

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: Overall, 1567 participants were screened and a total of 1472 participants started treatment with Radium-223

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set (SAF)

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 With Second Primary Malignancies (SPM), measured over From the initiation of Radium-223 (treatment period up to 6 months which includes 6 cycles every 4 weeks) up to 7 years after the last dose of Radium-223.

The primary endpoint is the number of participants with second primary malignancies. The registry defines a second primary malignancy as a new malignancy unrelated to prostate cancer or progression of prostate cancer. It states that all reported second primary malignancies are summarized as assessed by the physician, regardless of their relationship to Radium-223.

A participant count is a direct way to describe how many people in the specified analysis population were recorded as having the event. It is not, on its own, a rate adjusted for time under observation or a comparison of risk between treatments. In a long-term observational study, the length and completeness of follow-up matter when interpreting such a count: participants may have different opportunities for an event to be observed. The registry record does not report a person-time rate or another time-adjusted estimate for this endpoint.

Tracking new malignancies is relevant to the study’s stated long-term safety question. The broad definition in the record includes all reported second primary malignancies, irrespective of their assessed relationship to Radium-223. Consequently, the endpoint is a measure of recorded occurrence, not a determination that treatment caused an event.

The endpoint timeframe extends from initiation of Radium-223 through the treatment period, described as up to 6 months and including 6 cycles every 4 weeks, and up to 7 years after the last dose. The registry record does not report the observed number of participants meeting the endpoint, the timing of those events, or an uncertainty estimate. The endpoint’s definition and timeframe are reported, but its result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count describe?

A count of participants with an event reports how many people were recorded as meeting an outcome definition. It is different from a rate that accounts for time at risk, and different from a treatment-effect estimate comparing groups. For the primary endpoint, the registry names the outcome as the number of participants with second primary malignancies, but does not report the observed count. The endpoint is therefore defined, but its result cannot be interpreted quantitatively from the registry record.

Why does the study design matter?

Random assignment can, in an appropriately conducted trial, help make groups comparable on average. This study is instead described as a single-arm observational cohort in routine clinical practice. There is no like-for-like control group, and allocation is not stated. Descriptive findings can characterize events recorded among treated participants, but they cannot distinguish the contribution of treatment from disease characteristics, other care, or factors related to who received treatment and how long they were observed.

How should an uncertainty interval be understood?

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision for that estimate, while a wider interval indicates less precision. An interval does not correct a biased comparison, incomplete follow-up, or a mismatch between the study population and the question of interest. The registry record does not report a confidence interval for the primary endpoint, or a primary-endpoint estimate around which one could be interpreted.

Why are follow-up and the event definition important?

The primary endpoint concerns new malignancies that the physician assesses as unrelated to prostate cancer or its progression. The registry says all reported second primary malignancies are summarized regardless of their relationship to Radium-223. This definition distinguishes the endpoint from progression of the existing cancer, but the record does not describe an independent adjudication process or provide event-level detail. It also specifies observation through 7 years after the last dose. In general, an event count is easier to interpret when the amount of observation and the handling of participants lost to follow-up are clear. Those details are not reported in the registry record.

What do the planning illustrations represent?

Planning illustrations based on an observed effect are not observed power and are not evidence that the original study was designed to detect that effect. The stated assumptions for the illustrations are 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 this single-arm observational study’s actual design. The registry record does not report a study-specific sample-size justification or say that the study used these assumptions to plan enrollment.

The stated illustration method distinguishes time-to-event outcomes, for which the total number of events is used under a Schoenfeld approach, from other outcomes, for which the illustration gives participants per arm. Any such arm-based planning scenario should not be mistaken for an actual comparator in this study. Nor should a planning figure be read as an observed result or as a guarantee of precision.

What is missing for a fuller statistical assessment?

The record lists 13 outcome measures but reports no analyses. It does not report a primary-endpoint result, outcome-specific uncertainty estimates, the prespecified statistical analysis plan, an approach to multiplicity, or methods for missing data. The absence of these details means the reader cannot assess from the registry record whether analyses followed a prespecified plan, how incomplete follow-up was handled, or how much uncertainty surrounds the reported outcomes. General statistical principles can explain what those methods would address, but cannot fill in methods or results that are not reported.

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("Radium-223")
n      <- c(1472)
events <- c(24)
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  Radium-223  1472  24  1.6  1.0  2.4  1.1  2.4  1.1  2.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 13 outcome measures, including the primary endpoint and secondary outcomes such as overall survival, pain measures, bone fractures, and bone-associated events. When multiple outcomes are examined, the chance of observing an apparently notable result can depend on how many comparisons are made and how analyses are selected. Statistical approaches to multiplicity can address that issue, but the registry record does not report a multiplicity plan or any analyses.

The record identifies the primary endpoint as the number of participants with second primary malignancies. However, it does not report the observed result, an analysis method, or whether any outcome was designated for a particular inferential procedure. No interim analyses are reported in the registry record. Their absence from the record should not be interpreted as proof that none took place.

The primary outcome names the safety analysis set, but the record does not report its definition or its size. It also does not describe how participants with incomplete follow-up, missing outcome information, or discontinuation were handled. In general, missingness can affect both the number of events observed and the interpretation of the population to which results apply. The registry record does not report imputation, censoring, or sensitivity-analysis methods for these issues.

The enrollment figure is 1472, but enrollment alone does not establish how many participants contributed to each outcome or for how long. The record’s adverse-event entries list 1472 at risk for the Radium-223 group; the registry does not provide additional outcome-specific follow-up detail in the information reported. These omissions limit assessment of completeness, multiplicity, and precision.

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: anaemia (1.8%), prostate cancer (1.1%), general physical health deterioration (1.0%), pneumonia (1.0%), spinal cord compression (0.9%).

The adverse-event record lists 1472 participants at risk in the Radium-223 group, 325 affected under the serious adverse-event category, 837 affected under the other adverse-event category, and 1308 deaths. These are registry counts. The record does not provide enough detail to infer from these entries whether the categories overlap, when events occurred, or whether deaths were attributed to an adverse event or to Radium-223. The figures should not be added together or treated as separate, non-overlapping groups.

For serious adverse events, the listed terms and percentages are anaemia, 1.8%; prostate cancer, 1.1%; general physical health deterioration, 1.0%; pneumonia, 1.0%; spinal cord compression, 0.9%; and back pain, 0.7%. These percentages are reported as term-specific figures. They do not, on their own, establish causation or provide a comparison with an untreated group. The record does not explain the basis for the percentages or give additional information about duration of follow-up for these terms.

In general, adverse-event counts describe events recorded under a study’s reporting approach; interpretation depends on definitions, observation time, and the population included. Those details are not fully reported in the registry record. The entries therefore describe what the record lists, not an estimate of treatment-attributable risk.

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

The record establishes that this was an observational safety study of Radium-223 in routine clinical practice among people with metastatic castration-resistant prostate cancer and bone metastases. It defines the primary endpoint as the number of participants with second primary malignancies and gives a follow-up timeframe extending up to 7 years after the last dose. It also lists adverse-event counts, deaths, and several serious adverse-event terms with percentages.

However, the registry record does not report the result for the primary endpoint. It therefore does not establish how many participants had a second primary malignancy, the frequency of that outcome, or its precision. The listed adverse-event figures likewise do not establish that Radium-223 caused the events or deaths. The record does not include a comparable control group or a randomized treatment contrast from which to estimate a difference in outcomes.

In general, observed events in an observational cohort can be useful for describing what was recorded in routine practice. But comparisons with other settings or treatments require care: populations, observation periods, outcome definitions, and methods for collecting events may differ. The registry record does not report enough information to make such a comparison for the primary endpoint.

The listed secondary outcomes indicate topics the study tracked or planned to assess, including overall survival, pain, fractures, and bone-associated events. Their listing does not supply their results. The record reports no analyses, and it does not describe a statistical analysis plan, missing-data approach, or multiplicity method. The available information therefore supports a description of the study design and selected safety entries, but not a conclusion about comparative benefit, causal harm, or the size of risk for second primary malignancies.

14. Why This Trial Matters Statistically

Long-term safety questions are important to describe because some outcomes may be observed well after treatment begins or ends. This study’s stated follow-up for second primary malignancies extends from initiation of Radium-223 through treatment and up to 7 years after the last dose. Its routine-practice observational design addresses a different question from a randomized efficacy comparison: what events were recorded in a treated cohort over the specified period?

The statistical distinction matters. A count of participants with an event can describe the recorded burden in a cohort, but cannot establish whether treatment caused the event. Without a like-for-like comparator, the observed outcomes cannot be separated from underlying cancer, other care, or participant characteristics. That limitation is especially relevant when interpreting an outcome defined by physician assessment and summarized regardless of its relationship to Radium-223.

The record also illustrates why outcome definitions and analysis details are part of interpreting safety results. It names the primary outcome and the safety analysis set, but does not report the primary-endpoint count, uncertainty estimate, analysis plan, or missing-data approach. It lists 13 outcome measures and no analyses. Those gaps make it difficult to assess the precision and completeness of the findings from the registry record alone.

The adverse-event entries offer some descriptive information, including the listed serious-event counts and term-specific percentages. Their value is bounded by the lack of reported attribution, comparison, and follow-up detail. The study is therefore statistically informative as a clearly identified observational safety question, while the available registry results do not answer its primary question quantitatively.

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 main limitation is that the registry record does not report the primary endpoint result. Although it defines second primary malignancies and gives the observation window, it provides no event count, risk estimate, or uncertainty interval for that outcome. The stated primary safety question therefore cannot be answered numerically from the record.

The single-arm observational design has no like-for-like control group. It cannot separate treatment effects from disease progression, participant characteristics, or other aspects of routine care. Allocation is not stated, and the registry cautions that arms are not a like-for-like control comparison. No adjusted comparative analysis is reported.

Important details about follow-up and analysis are also not reported in the registry record. The enrollment figure does not show how many participants contributed to each outcome, how much observation time they contributed, or how incomplete follow-up was handled. The record names a safety analysis set but does not define it. It does not describe missing-data methods, outcome adjudication beyond physician assessment, or whether event ascertainment was consistent over the long follow-up period.

The record lists 13 outcome measures and no analyses, and does not report a statistical analysis plan or multiplicity approach. This makes it impossible to assess from the record whether the reported outcomes and analyses reflect prespecified methods. The serious adverse-event counts and term percentages are descriptive entries, without reported attribution or a comparator. These limitations restrict causal interpretation and assessment of the precision, completeness, and broader applicability of the reported safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Observational Study for the Evaluation of Long-term Safety of Radium-223 Used for the Treatment of Metastatic Castration Resistant Prostate Cancer — NCT02141438.
• Registry record last updated 2025-10-16; status last verified 2025-10.
• Results first posted 2025-09-05.
• 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 record describes NCT02141438, a completed, single-arm observational study of Radium-223 dichloride in routine clinical practice for metastatic castration-resistant prostate cancer with bone metastases. Enrollment was 1472. The study began on 2014-08-20, with primary completion on 2024-08-02.

The primary outcome is the number of participants with second primary malignancies, defined as new malignancies unrelated to prostate cancer or its progression. The specified timeframe extends from initiation of treatment through the treatment period and up to 7 years after the last dose. The primary outcome result is not reported in the registry record.

The record lists 13 outcome measures and no analyses. It reports adverse-event entries for the Radium-223 group, including 325 affected under the serious category, 837 under the other category, and 1308 deaths; it also lists serious-event terms with percentages. There is no like-for-like control group, and the record does not report an adjusted comparison or a primary-endpoint uncertainty estimate.