Open Label Extension to SRE Studies in United Kingdom and Czech Republic Only: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open Label Extension to SRE Studies in United Kingdom and Czech Republic Only (NCT00950911), a na phase 3 study. The primary outcome is Number of Participants Survived.

2. Clinical Question

3. Trial Design

This was a Phase 3, open-label extension study, described in its title as taking place in the United Kingdom and Czech Republic. The registry record lists the study as completed, with a start date of 2009-07 and primary completion of 2012-02. Enrollment was 35. The official title describes a single-arm study of long-term denosumab safety in people with bone metastases and advanced cancer or multiple myeloma.

Although the safety results are grouped under two treatment-sequence labels, the design is not a randomized comparison. One label is Zoledronic Acid 4 mg Q4W / Denosumab 120 mg Q4W; the other is Denosumab 120 mg Q4W / Denosumab 120 mg Q4W. Allocation is listed as not applicable, and masking is listed as none. Participants and study personnel therefore were not masked according to the registry record. The record does not explain how participants came to receive their prior treatment or enter either sequence group.

The study purpose emphasizes safety and tolerability, including adverse events, immunogenicity, and safety laboratory parameters. The one registered outcome measure is the number of participants survived, with a 2 years timeframe and the Full Analysis Set named as the population. Details of the protocol, treatment follow-up, and the relationship between that outcome and the stated safety purpose are not reported in the registry record. The record lists no statistical analyses. These design features support a descriptive reading of the posted counts, not a causal estimate of differences between treatment histories.

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: Full Analysis Set

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 Survived, measured over 2 years.

The registered primary endpoint is the number of participants who survived, measured over 2 years. It is a count of participants, rather than a reported time-to-event estimate: the registry record does not provide a survival proportion, a time-to-event analysis, or the count itself. The named analysis population is the Full Analysis Set, but its definition and the number of participants included in it are not reported in the registry record.

As a general statistical concept, survival is an important outcome because it records whether participants are alive at a specified assessment or period. A count alone, however, is difficult to interpret without knowing the population denominator, how survival status was determined, how missing status was handled, and whether the measure represents status at a particular time or survival throughout follow-up. Those details are not reported in the registry record.

The stated purpose centers on safety and tolerability, while the registered primary outcome is survival. The record does not explain this difference or report a primary-outcome result. It therefore does not support an estimate of survival or an inference about how denosumab affected survival.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a single-group, open-label extension and lists no statistical analyses. The methods below explain how the posted measures are generally interpreted; they do not imply that any unreported analysis was performed for this study.

What do participant counts represent?

A participant count records how many people in a stated group met an outcome definition. For the safety results, the record gives a number at risk and a number affected. The number at risk is the reported denominator for that group and outcome, while the number affected is the reported count of participants with an event. These are not necessarily the same as counts of individual event episodes: a participant may experience more than one event, but the posted participant count does not convey how many episodes occurred.

For a binary outcome such as survival status, the count is most informative when its denominator and outcome definition are also clear. A proportion can be estimated from a count and denominator, but no new estimate is needed to interpret the registry record, and no primary survival count is posted. The named population is the Full Analysis Set; how that set was defined and how many participants it contained are not reported in the registry record.

How should uncertainty be understood?

As a general statistical concept, a confidence interval describes the range of values reasonably compatible with observed data under a specified statistical model and procedure. It helps distinguish a precise estimate from one with substantial uncertainty. Small groups often yield imprecise estimates, even when the observed counts look clear. No confidence intervals are reported for the primary endpoint or adverse-event counts, so their precision cannot be assessed from the registry record using intervals.

A p-value, when reported, evaluates how compatible data are with a specified null hypothesis under the assumptions of a statistical test. It does not measure the probability that a treatment works, and it does not establish clinical importance. No p-values or testing procedures are reported in the registry record. The absence of a test is especially relevant because the study is not randomized and the treatment-sequence labels do not form a like-for-like control comparison.

Why does the design matter for comparisons?

Random allocation can help balance prognostic characteristics between groups, on average, and supports a more credible causal comparison. Here, allocation is listed as not applicable and the study is described as single-group. The groups are identified by treatment sequences, including different prior-treatment histories. A difference in their observed event counts could therefore reflect who entered each sequence, differences in prior treatment, follow-up, or other factors, as well as any treatment-related effect. The registry record does not report an adjusted analysis that could address such differences.

Open-label status means masking is listed as none. As a general matter, knowledge of treatment can influence reporting, assessment, or clinical management, particularly for outcomes that require judgment. The record does not describe how adverse events were assessed or whether any safeguards were used to reduce assessment bias. This is a limitation to consider, not evidence that a particular event report was biased.

What do planning illustrations mean?

Sample-size planning asks how many participants might be needed under specified assumptions to detect a target effect with a chosen design and analysis. The planning assumptions associated with this record describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of an observed effect. Any resulting sample-size figures are planning illustrations, not observed power and not evidence that the study was designed or analyzed using those assumptions.

Those assumptions describe a hypothetical comparison, whereas this study is not a randomized comparison and is registered as single-group. A planning calculation cannot repair that design limitation or turn the treatment-sequence groups into randomized arms. The registry record does not report the trial's own sample-size justification, so it is not possible to determine whether the illustration reflects the original design rationale.

What does a missing analysis leave unresolved?

Without a posted primary result, an analysis population count, or an analysis method, there is no basis for estimating the survival outcome or its precision. Without a reported approach to missing data, it is not possible to determine whether participants with unknown outcome status were excluded, handled in another way, or absent. Those questions should remain open rather than being answered by assumptions about standard practice.

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("Zoledronic Acid 4 mg Q4W / Denosumab 120 mg Q4W", "Denosumab 120 mg Q4W / Denosumab 120 mg Q4W")
n      <- c(17, 18)
events <- c(13, 12)
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  Zoledronic Acid 4 mg Q4W / Denosumab 120 mg Q4W  17  13  76.5  50.1  93.2  52.7  90.4  52.4  90.3
ARM  Denosumab 120 mg Q4W / Denosumab 120 mg Q4W  18  12  66.7  41.0  86.7  43.7  83.7  43.4  83.7

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and no statistical analyses. It does not report a statistical testing plan, a hierarchy of outcomes, or any adjustment for multiple comparisons. The study purpose includes adverse events, immunogenicity, and safety laboratory parameters, but the record does not provide results or analysis details for all of those domains. It is therefore not possible to assess how many outcomes were examined or how the investigators handled the chance of false-positive findings across multiple tests.

As a general statistical concept, multiplicity arises when many hypotheses or outcomes are tested: the chance of at least one apparently unusual result can increase when each test is considered separately. A prespecified hierarchy or adjustment can address that issue, but no such approach is reported in the registry record. The listed serious adverse-event terms should be treated as descriptive entries, not as results of a documented set of hypothesis tests.

The primary outcome names the Full Analysis Set, but the set's definition and participant count are not reported in the registry record. Missing-data methods, the number of participants with unknown survival status, and the handling of incomplete safety follow-up are also not reported. No conclusion about completeness can be drawn from these omissions. The registry record does not report interim analyses or stopping rules, and there is no basis for assuming either was or was not used.

These reporting gaps limit interpretation: the primary endpoint cannot be reconstructed, uncertainty cannot be evaluated, and the analysis choices cannot be checked against a stated plan. They also prevent a meaningful assessment of whether the posted safety summaries cover the same participants or follow-up periods across the listed groups.

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: osteonecrosis of jaw (11.8%), cachexia (11.1%), atrial fibrillation (5.9%), cardiac failure (5.9%), death (5.9%).

The serious adverse-event figures are participant counts within each listed safety group. For Zoledronic Acid 4 mg Q4W / Denosumab 120 mg Q4W, 8 participants were affected among 17 at risk. For Denosumab 120 mg Q4W / Denosumab 120 mg Q4W, 10 were affected among 18 at risk. The figures for other adverse events are 13 of 17 and 13 of 18, respectively. These counts should not be confused with the number of event episodes, and the registry record does not report a statistical comparison between the groups.

The registry also lists serious adverse-event terms and percentages: Osteonecrosis of jaw, 11.8%; Cachexia, 11.1%; Atrial fibrillation, 5.9%; Cardiac failure, 5.9%; Death, 5.9%; and Convulsion, 5.9%. The record does not show a treatment-group denominator for each listed term in the information reported. The percentages therefore should not be assigned to a particular group or used to compare groups.

As a general concept, an adverse event is an event recorded during a study; its occurrence alone does not establish that treatment caused it. The registry record does not report causal attribution for these terms. The figures describe what was recorded, not an estimate of treatment-caused risk.

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

The results support a narrow descriptive reading of safety: the registry record reports how many participants in each treatment-sequence group were affected by serious and other adverse events, and it lists several serious-event terms with percentages. It does not report a primary survival count, an analysis of survival, or statistical uncertainty around the safety counts. As a result, the precision and broader implications of these observations cannot be established from the posted results.

The treatment-sequence groups are not randomized like-for-like controls. Their observed counts cannot establish that one sequence caused more or fewer events than the other, and they cannot isolate the effect of denosumab from differences in prior treatment or participant history. The record also does not establish that an adverse event was caused by treatment. A descriptive event listing should not be converted into a causal claim.

The registered primary endpoint is the number of participants survived over 2 years, but its result is not reported in the registry record. The adverse-event figures do not answer that survival question. Nor does the listed serious-event term Death, with its percentage, supply the missing survival outcome: the record does not give the relevant denominator, group assignment, or relationship to survival status for that term.

Conversely, the lack of a posted primary result does not show that there were no outcomes or events. It means the registry record does not provide enough information to evaluate that endpoint. The results also do not establish equivalence between treatment histories, demonstrate efficacy, or support conclusions beyond the recorded groups and measures. The interpretation should remain limited to the stated counts and the explicit gaps in the record.

14. Why This Trial Matters Statistically

This study illustrates why design labels and outcome reporting matter as much as numerical results. The record describes an open-label, single-group extension, yet its safety outcomes are organized under two treatment-sequence labels. Recognizing that those labels are not randomized comparison arms prevents descriptive counts from being mistaken for a causal contrast.

It also illustrates the importance of matching a study's stated purpose to its registered endpoint. The purpose concerns safety and tolerability, including adverse events, immunogenicity, and laboratory parameters; the listed primary endpoint is the number of participants who survived over 2 years. With no primary result or analysis posted, readers cannot evaluate that endpoint or determine how it relates to the safety objective.

Finally, counts without uncertainty and analysis details have limited inferential value. The serious-event counts are useful as a record of what was reported, but the registry does not provide confidence intervals, tests, missing-data handling, or a statistical comparison. For biostatistical interpretation, identifying what the record does not establish is part of accurately reading what it does report.

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 registry record does not report the primary survival count, the denominator analyzed for that endpoint, or an uncertainty estimate. The Full Analysis Set is named, but its definition and size are not given. The record also does not report participant flow, the extent of missing outcome data, or methods for handling missingness. These gaps prevent reconstruction of the primary result.

The study is open label and not randomized, and the safety groups are treatment sequences rather than like-for-like control arms. The record does not explain treatment assignment, group entry, prior-treatment timing, or whether the groups differed in relevant participant characteristics. This limits comparisons between their event counts. Details of outcome assessment, adverse-event attribution, and follow-up completeness are also not reported in the registry record.

Although the purpose mentions immunogenicity and safety laboratory parameters, the posted information summarized in the registry record does not provide results for those measures. It also does not report a multiplicity approach, a statistical analysis plan, a sample-size justification, interim analyses, or stopping rules. These omissions do not establish that such procedures were absent; they mean they cannot be assessed from the registry record. The posted safety counts are consequently best treated as descriptive observations, with no basis for broader causal or efficacy conclusions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Open Label Extension to SRE Studies in United Kingdom and Czech Republic Only — NCT00950911.
• Registry record last updated 2014-02-11; status last verified 2013-12.
• Results first posted 2014-02-11.
• 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 record describes a completed Phase 3, open-label, single-group extension study of denosumab in participants with bone metastases and advanced cancer or multiple myeloma. Enrollment was 35. Safety results are grouped by two treatment sequences, but the design is not a randomized comparison.

The stated purpose is to describe safety and tolerability. The registered primary outcome is the number of participants who survived over 2 years in the Full Analysis Set; its result is not reported in the registry record. The record lists participant counts for serious and other adverse events and several serious-event terms with percentages, but no statistical analyses, uncertainty estimates, or comparative tests. Interpretation is therefore descriptive and limited by missing endpoint, analysis, and follow-up details.