Effect of Denosumab on Cellular Biomarkers in the Human Breast: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Denosumab on Cellular Biomarkers in the Human Breast (NCT02099461), a randomized phase 1 study. The primary outcome is Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells.

2. Clinical Question

This question concerns a cellular biomarker rather than a clinical health outcome. The posted outcome describes the percentage of Ki-67-positive cells in specified breast tissue structures, and a higher percentage indicates a higher rate of epithelial cell proliferation. The comparison therefore asks whether the measured change in this biomarker differed between the treatment groups and the no-treatment group.

The trial was randomized, stratified, parallel-group, and multicenter according to its official title. The registry record does not report the stratification factors, so their role cannot be evaluated from the posted information. The clinical question is limited to the measured biomarker over the stated follow-up; the registry record does not report a question about longer-term outcomes.

3. Trial Design

This was a randomized, open-label, parallel-group phase 1 trial. The registry record lists an enrollment of 82 and identifies the population as healthy female volunteers. It describes the study as multicenter. Participants were assigned to no treatment, denosumab 60 mg, or denosumab 120 mg. The intervention groups received a subcutaneous injection on Day 1; the no-treatment group received no study treatment.

All three groups underwent percutaneous core needle breast biopsies on Day 1 and Day 28. For participants assigned to denosumab, the Day 1 biopsy occurred before treatment. The primary outcome was measured at baseline and Day 28. The registry record marks the trial completed and lists its phase as phase 1. Its recorded start was 2014-04 and primary completion was 2014-07.

The open-label design means masking was not used. The comparator was no treatment rather than a placebo treatment, as described in the registry. The record identifies randomization and stratification, but does not report the allocation sequence, concealment procedures, stratification factors, or any steps used to limit bias in the measurement or analysis.

The primary outcome analysis population is described as the pharmacodynamic analysis set with non-missing data. Outcome group counts were 25.0 for no treatment, 25.0 for denosumab 60 mg, and 26.0 for denosumab 120 mg. The registry record does not explain why the analysis set differs from the enrollment figure or report missing outcome counts. These group counts should be understood as outcome-specific analysis counts, not as a description of every participant’s trial experience.

The registry record lists one outcome measure and no secondary outcome measures. It does not report the trial’s original sample-size justification, its planned statistical analysis details, or whether any interim analyses were conducted. Those design features cannot be inferred from the posted outcome results.

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: On study day 1, eligible participants were randomized into 1 of 3 treatment assignments. Randomization was stratified by average length of menstrual cycle (\< 28 days, equal to 28 days, and \> 28 days).

Overall Study

Analysis population for the primary outcome, as defined in the registry: Pharmacodynamic analysis set with non-missing data

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 Log Ratio of Post-baseline to Baseline Ki-67 Index in Mammary Epithelial Cells, measured over Baseline and Day 28.

The primary endpoint is the log ratio of the post-baseline to baseline Ki-67 index in mammary epithelial cells, measured at baseline and Day 28. Ki-67 is a marker of cell proliferation. Tissue was collected by percutaneous core needle breast biopsy, and Ki-67 was measured using immunohistochemical staining and digital imaging.

The proliferation index was calculated as the percentage of Ki-67-positive terminal ductal lobular unit and duct epithelial cells. A higher percentage indicates a higher rate of epithelial cell proliferation. Expressing the change as a log ratio represents the post-baseline measurement relative to the participant’s baseline measurement on a logarithmic scale. The posted outcome summarizes this continuous measure using a mean and standard deviation for each group.

In general, a biomarker endpoint can provide a way to quantify a biological response over a specified follow-up period. It is not itself a patient-centered clinical outcome. The registry record frames the endpoint as a test of whether denosumab is associated with a decrease in proliferation compared with no treatment. The results therefore speak to the measured tissue biomarker at Day 28, not to outcomes or effects that were not measured in the posted endpoint.

The registry record does not explain why this particular biomarker, tissue sampling approach, or follow-up interval was selected, nor does it report further details about assay validation or interpretation thresholds. Those matters are not reported in the registry record.

7. Results Posted in the Registry

• Denosumab 60 mg: mean -0.10 versus 0.08 on control; difference -0.18 (95% CI -0.67 to 0.30), standardized effect d = -0.21; z-test p = 0.455.
• Denosumab 120 mg: mean -0.08 versus 0.08 on control; difference -0.17 (95% CI -0.60 to 0.27), standardized effect d = -0.21; z-test p = 0.456.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous, and the registry summarizes it with a mean and standard deviation. In general, a mean describes the center of a set of measurements, while a standard deviation describes how spread out individual measurements are around that mean. The posted group means are 0.084 for no treatment, -0.1 for denosumab 60 mg, and -0.081 for denosumab 120 mg. The associated standard deviations are 0.645, 1.048, and 0.918. The spread within each group is relevant because variability affects how precisely group comparisons can be estimated.

The unadjusted recalculation compares the mean in each denosumab group with the mean in the no-treatment group. For denosumab 60 mg, the recalculated difference is -0.184; for denosumab 120 mg, it is -0.165. These calculations use the posted group summaries and are not adjusted for other variables. The corresponding unadjusted p-values are 0.455 and 0.456. A p-value describes how compatible the data are with a specified null model under the assumptions of the test; it is not the probability that a treatment effect is true, and it does not measure the size or clinical importance of a difference.

The registry’s own reported analysis is ANCOVA, short for analysis of covariance. In general, ANCOVA estimates group comparisons while accounting for one or more covariates included in the model. The registry reports least-squares means for each group and least-squares mean differences for the two comparisons with no treatment. These adjusted quantities need not equal the crude group means or unadjusted differences. The registry record does not identify the covariates, model specification, treatment of baseline measurements, or other model details. Those details are not reported in the registry record, so the reported ANCOVA cannot be fully reproduced from the posted information.

The reported least-squares means are 0.15 for no treatment, -0.16 for denosumab 60 mg, and -0.09 for denosumab 120 mg. The reported least-squares mean difference is -0.31 for the no-treatment/60 mg pair, with a 95% confidence interval from -0.720 to 0.098. For the no-treatment/120 mg pair, the reported difference is -0.24, with a 95% confidence interval from -0.646 to 0.161. An adjusted contrast is an estimate on the endpoint scale; its interval represents uncertainty around that estimate under the fitted analysis.

In general, a confidence interval conveys a range of values that are reasonably compatible with the observed data and the method’s assumptions. An interval that includes zero does not establish that the groups are equivalent. It indicates that the data and method do not rule out zero as a value for the contrast at the interval’s stated confidence level. The interval also permits nonzero values, and its width matters when judging precision.

Over-dispersion is a general concern when data vary more than a model assumes. In general, excess variability can make standard errors too small if a model fails to account for it, leading to overly narrow intervals and optimistic tests. This endpoint is reported as a continuous measure with group standard deviations, and the registry reports ANCOVA. The record does not report a separate assessment of over-dispersion or a model diagnostic, so no such issue can be confirmed from the registry information.

The comparison is between each denosumab dose and a no-treatment control, not between the two denosumab doses. The registry gives separate results for each control comparison. In general, making multiple comparisons can increase the chance of at least one false-positive result if no adjustment or other multiplicity strategy is used. The registry record does not report a multiplicity procedure, so it is not possible to determine whether or how the comparisons were adjusted as a family.

The outcome analysis population is the pharmacodynamic analysis set with non-missing data. In general, analyzing only participants with non-missing outcome data can affect interpretation if missingness is related to treatment or outcome. The registry record does not report the number of missing values, reasons for missingness, imputation procedures, or sensitivity analyses. The effect of missing data on the estimates therefore cannot be assessed from the posted record.

Randomization supports comparison of assigned groups, but the registry entry alone does not establish that all practical aspects of allocation and follow-up were free of bias. The record identifies the design as randomized and stratified, but does not report the sequence-generation or concealment methods or the stratification factors. It also identifies the study as open-label. These design details should be kept in view when interpreting an outcome measured from tissue samples and analyzed in a defined pharmacodynamic population.

General statistical interpretation should distinguish the estimate, its uncertainty, and the analysis method. The unadjusted recalculations are based on summary statistics, while the sponsor’s reported registry analyses use ANCOVA. Neither a p-value alone nor a point estimate alone describes the full evidence. The record does not report enough methodological detail to reconstruct the adjusted model or assess every analysis assumption.

10. Confidence Intervals and Precision

The registry reports 95% confidence intervals for the ANCOVA contrasts. For denosumab 60 mg versus no treatment, the least-squares mean difference is -0.31, with an interval from -0.720 to 0.098. For denosumab 120 mg versus no treatment, the difference is -0.24, with an interval from -0.646 to 0.161. Each interval includes zero and also extends to values on either side of zero. The posted results therefore leave uncertainty about the direction and size of the adjusted contrast.

In general, a confidence interval describes the precision of an estimate under the analysis method and its assumptions. A narrower interval indicates greater precision than a wider interval on the same scale. Whether a particular interval is narrow enough to be useful depends on the range of effects that would matter for the scientific question; the registry record does not report a threshold for interpreting the Ki-67 contrast.

The group standard deviations are 0.645 for no treatment, 1.048 for denosumab 60 mg, and 0.918 for denosumab 120 mg. The posted analysis counts are 25.0, 25.0, and 26.0, respectively. These group summaries provide context for the variability and amount of data underlying the outcome estimates, but they do not explain all uncertainty in the adjusted ANCOVA results.

The recalculated unadjusted mean differences are -0.184 and -0.165, with unadjusted p-values of 0.455 and 0.456. The registry’s adjusted contrast estimates and intervals are different from those recalculations. Precision should therefore be described using the interval from the analysis being discussed, rather than attaching the registry’s ANCOVA intervals to the recalculated unadjusted estimates.

The registry record does not report confidence intervals for the group-level means, nor does it provide enough ANCOVA details to reproduce the adjusted intervals. It also does not report a clinically meaningful threshold for the endpoint. Thus, the intervals characterize statistical uncertainty on the log-ratio scale, but the registry alone does not establish how much of that range would be important in a clinical or biological sense.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrative sample sizes per arm for the two-group comparisons, not total event counts. They are based on a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. These are planning assumptions for the illustration; the trial’s original design assumptions are not reported in the registry record.

For the 60 mg comparison, planning for 100% of the observed effect gives 352 participants per arm for 80% power and 470 participants per arm for 90% power. Planning for 75% of the observed effect gives 625 participants per arm for 80% power and 836 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,405 participants per arm for 80% power and 1,880 participants per arm for 90% power.

For the 120 mg comparison, planning for 100% of the observed effect gives 366 participants per arm for 80% power and 490 participants per arm for 90% power. Planning for 75% of the observed effect gives 650 participants per arm for 80% power and 870 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,462 participants per arm for 80% power and 1,957 participants per arm for 90% power.

In plain terms, the 80% power column gives the planned number per arm under the stated assumptions for a design with an 80% chance of detecting the specified effect if that effect is present. The 90% power column gives the corresponding number per arm for a design with a 90% chance under those assumptions. Smaller effects require more participants because they are harder to distinguish from random variation. These are planning illustrations based on the observed effect, not observed power.

The registry record does not report the assumptions used when the trial itself was designed, so these figures should not be read as the trial’s original target or as evidence about why the trial enrolled its recorded number of participants. The planning values are sensitive to the observed effect used as their starting point, and the observed effect may not be a stable estimate of the effect a future study would encounter.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.184; pooled standard deviation σ = 0.870.
2. n = 2 × (1.96 + 0.842)² × 0.870² / -0.184² = 351.1, rounded up to 352 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.184                      # observed difference in means
sigma <- 0.870151998216404                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2099461)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 352 (80% power), 470 (90% power)
 75% of observed effect: n per arm = 625 (80% power), 836 (90% power)
 50% of observed effect: n per arm = 1,405 (80% power), 1,880 (90% power)
power.t.test: 352 
Simulated power at n = 352 per arm: 0.801 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry reports the sponsor’s analysis as ANCOVA, with least-squares means and least-squares mean differences. The reported group means are 0.15 for no treatment, -0.16 for denosumab 60 mg, and -0.09 for denosumab 120 mg. The reported contrasts are -0.31 for the no-treatment/60 mg comparison and -0.24 for the no-treatment/120 mg comparison. Their 95% confidence intervals are -0.720 to 0.098 and -0.646 to 0.161.

The unadjusted recalculations use the posted group means and standard deviations rather than the ANCOVA model. They give mean differences of -0.184 and -0.165, with unadjusted p-values of 0.455 and 0.456. Because the methods differ, the recalculated values should not be presented as replacements for the registry’s reported ANCOVA results. The record does not give enough model detail to reproduce the sponsor’s adjusted estimates.

The registry record does not mark a discrepancy between its reported results and the simple recalculations. Still, the two sets of estimates answer the comparison using different analyses. The sponsor’s reported results are the registry’s ANCOVA results; the recalculations are supplementary unadjusted comparisons from summary statistics. Their differences should be interpreted as a distinction between analysis methods, not as a second independent trial result.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and five analyses. The analyses include ANCOVA results for the three groups and two contrasts comparing denosumab groups with no treatment. No secondary outcome measures are posted. The registry record does not report a multiplicity adjustment, a prespecified testing hierarchy, or a rule for controlling the overall chance of a false-positive finding across comparisons.

In general, when several statistical comparisons are made, the chance of at least one apparently positive result can increase unless the analysis plan accounts for the family of tests. This does not determine the validity of any individual result, but it is relevant to how a set of results should be interpreted. Since no adjustment strategy is reported, the posted analyses should be read as separate results without assuming family-wise error control.

The primary outcome population is described as the pharmacodynamic analysis set with non-missing data. The outcome group counts are 25.0 for no treatment, 25.0 for denosumab 60 mg, and 26.0 for denosumab 120 mg. The registry record does not report how many participants had missing endpoint data, why data were missing, whether missingness differed by group, or how missing values were handled. It does not report sensitivity analyses for missing data.

In general, excluding participants without observed outcome data can affect a comparison if the availability of data is related to treatment assignment or the endpoint. Without information about missingness and its handling, the direction or magnitude of any such effect cannot be assessed. The analysis-set description is important context, but it does not establish that missingness was absent or harmless.

The registry identifies the study as randomized and stratified, but does not report the analysis population rules in further detail, the stratification factors, or whether the posted analyses follow an intention-to-treat principle. It also does not report the ANCOVA covariates or model specification. Those details are not reported in the registry record, limiting assessment of whether the analysis followed a prespecified plan and how robust the adjusted results are to alternative choices.

15. 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 non-serious adverse event terms

The registry lists serious adverse event counts of 0 in each group. The corresponding numbers at risk are 27 for no treatment, 27 for denosumab 60 mg, and 28 for denosumab 120 mg. The listed serious adverse event terms are empty. The registry record therefore does not identify a serious adverse event term in these entries; it does not provide a narrative explanation for the empty term list.

For other adverse events, the registry lists 4 participants affected among 27 at risk in the no-treatment group, 6 among 27 at risk in the 60 mg group, and 11 among 28 at risk in the 120 mg group. These are the posted counts. They should be read separately from the serious adverse event counts and are not a description of event severity beyond the registry’s classification.

The adverse event group labels in the registry differ in wording from the primary outcome arm labels. The record does not report death counts as numeric values, so deaths are not reported in the registry record. It also does not provide event-level descriptions for the other adverse events in the registry record by these counts. These entries alone do not characterize the full safety profile or establish a causal relationship between treatment and an event.

In general, adverse event counts are interpreted in relation to the groups observed, the period of collection, and the event definitions. The registry information quoted does not provide additional detail on those aspects, so the counts should not be extended beyond the entries recorded.

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

The posted results show the mean log-ratio Ki-67 endpoint and its variability in the no-treatment and denosumab groups at Day 28. The unadjusted recalculated differences are negative for both dose comparisons: -0.184 for denosumab 60 mg and -0.165 for denosumab 120 mg versus no treatment. The registry’s ANCOVA contrasts are also negative, at -0.31 and -0.24, respectively. These are estimates on the endpoint’s log-ratio scale.

The registry’s 95% confidence intervals for both adjusted contrasts include zero: -0.720 to 0.098 for the 60 mg comparison and -0.646 to 0.161 for the 120 mg comparison. Thus, the intervals do not rule out a zero contrast, and they also include values on either side of zero. The registry’s unadjusted p-values are 0.455 and 0.456. Neither the p-values nor the intervals by themselves establish that the groups are equivalent, or that a particular difference is clinically or biologically important.

The endpoint is a tissue biomarker measured at baseline and Day 28. It is not a clinical outcome, and the registry does not report whether the observed biomarker values correspond to a meaningful change in health. The trial therefore addresses a focused question about measured mammary epithelial cell proliferation, not a broader question about clinical benefit, long-term outcomes, or other populations.

The findings also depend on the analysis. The sponsor’s registry results use ANCOVA, while the recalculated differences are unadjusted. Since the registry does not report the ANCOVA covariates or model details, the adjusted results cannot be fully reconstructed from the record. Both analyses should be named accurately when discussed, and their estimates should not be treated as interchangeable.

Overall, the posted data provide estimates with substantial uncertainty on the endpoint scale. They do not establish a definitive direction or magnitude for the adjusted contrast, and they do not support conclusions beyond the measured outcome and follow-up described in the registry.

17. Why This Trial Matters Statistically

This trial illustrates how a randomized clinical study can address a narrow biological question using a continuous biomarker endpoint. The outcome is not simply a count of events: it is a log ratio derived from tissue measurements at baseline and Day 28. Its interpretation depends on understanding what was measured, the scale on which it was analyzed, and the population contributing data.

It also demonstrates why estimates and uncertainty should be considered together. The registry reports adjusted contrast estimates and confidence intervals, while summary statistics permit unadjusted recalculations. Those analyses yield different numerical estimates because they are not the same analysis. Clear separation of adjusted and unadjusted results helps prevent an apparent disagreement from being mistaken for a data inconsistency.

The study is also a useful setting for examining how a confidence interval that includes zero should be read. Such an interval does not prove no effect or equivalence. It communicates uncertainty across a range of possible contrast values. The registry does not provide a threshold for what would count as a meaningful change in this biomarker, so statistical uncertainty cannot be translated into a judgment about biological importance from the record alone.

Finally, the record highlights the importance of reporting analysis details. The outcome population is defined as a pharmacodynamic set with non-missing data, but missingness details and ANCOVA model specifications are not reported. Without those details, readers cannot fully assess reproducibility, the handling of incomplete outcomes, or the role of adjustment. These are central considerations when interpreting a small phase 1 biomarker study.

18. 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 endpoint is a cellular biomarker measured from breast tissue at baseline and Day 28. The registry record does not report a clinical outcome or longer-term follow-up for this endpoint. Conclusions should therefore remain specific to the measured Ki-67 log ratio over the recorded interval; the record does not establish how that biomarker relates to health outcomes.

The trial was open-label and used a no-treatment comparator. Masking was not used. The registry does not report procedures for blinded laboratory assessment, allocation concealment, or other safeguards that might affect bias. It also identifies the study as stratified but does not name the stratification factors.

The outcome analysis is restricted to the pharmacodynamic analysis set with non-missing data. The registry does not report missing outcome counts, reasons for missingness, handling procedures, or sensitivity analyses. It is consequently not possible to assess whether missing data could have influenced the comparisons.

The sponsor’s reported analysis is ANCOVA, but the model covariates and specification are not reported. The posted unadjusted recalculations are not substitutes for a reproducible adjusted analysis. The registry also does not report a multiplicity strategy, an original sample-size justification, or whether interim analyses were performed.

The posted group sizes for the outcome are 25.0, 25.0, and 26.0, and the group standard deviations are 0.645, 1.048, and 0.918. The confidence intervals for the adjusted contrasts include zero and extend to values on either side. The record does not define a threshold for a meaningful biomarker difference, which limits assessment of the practical significance of the estimates. These limitations do not negate the posted findings; they delimit what can be concluded from the registry information.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Effect of Denosumab on Cellular Biomarkers in the Human Breast — NCT02099461.
• Registry record last updated 2015-09-24; status last verified 2015-08.
• Results first posted 2015-09-24.
• 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.

22. Record Summary

The registry describes a completed, randomized, stratified, open-label, parallel-group, multicenter phase 1 trial of denosumab in healthy female volunteers. Participants were assigned to no treatment, denosumab 60 mg, or denosumab 120 mg, with breast biopsies at baseline and Day 28.

The primary endpoint was the log ratio of post-baseline to baseline Ki-67 index in mammary epithelial cells. The registry reports group means and standard deviations, ANCOVA least-squares means and contrasts, and adverse event counts. The adjusted contrast intervals include zero. Unadjusted recalculations are distinct from the registry’s ANCOVA analyses.

The record does not report the ANCOVA model details, missing-data handling, multiplicity strategy, or original sample-size justification. Interpretation is limited to the posted biomarker endpoint and follow-up.