Dose-finding Study of Empegfilgrastim for Neutropenia Prophylaxis in Patients With Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-finding Study of Empegfilgrastim for Neutropenia Prophylaxis in Patients With Breast Cancer (NCT01569087), a randomized phase 2 study. The primary outcome is CTCAE Grade 3/4 Neutropenia Incidence.

2. Clinical Question

3. Trial Design

The registry describes NCT01569087 as a randomized, multicenter, open-label Phase II clinical study with a parallel-group model. Its official title identifies the comparison as a single dose of Extimia® versus daily filgrastim for neutropenia prophylaxis in breast cancer patients receiving myelosuppressive chemotherapy. The record lists Biocad as sponsor and the study status as completed.

The registry records enrollment of 60. The study began in 2012-05, with primary completion in 2013-01. Participants were assigned to empegfilgrastim 3 mg, empegfilgrastim 6 mg, or filgrastim. The two empegfilgrastim regimens were single subcutaneous doses given 24 h after chemotherapy. Filgrastim was given subcutaneously each day, beginning 24 h after chemotherapy, until ANC 10 000/μL or for 14 days, whichever occurred first.

The main endpoint was the number of participants with CTCAE Grade 3/4 neutropenia during 21 days. The posted primary analysis population was modified intention-to-treat rather than all randomized participants: it included those who received at least 1 injection and excluded participants who missed blood sampling on visit 5, the expected time of nadir. The posted primary endpoint counts were 18 of 21 for empegfilgrastim 3 mg, 13 of 20 for empegfilgrastim 6 mg, and 11 of 18 for filgrastim.

Randomization and the parallel design describe the intended comparison, while open-label masking means the record identifies no masking. The registry record does not report the method used to generate or implement the random allocation, nor does it report the trial's original sample-size justification or full statistical analysis plan.

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

Analysis population for the primary outcome, as defined in the registry: Modified intention-to-treat population (analysis included patients who received at least 1 injection of study drug. Patients who had missed blood sampling on visit 5 \[expected time of nadir\] were excluded from analysis)

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 CTCAE Grade 3/4 Neutropenia Incidence, measured over 21 days.

The primary endpoint counts participants who experienced CTCAE Grade 3/4 neutropenia during the 21-day timeframe. It is a binary outcome at the participant level: each person is counted according to whether the event occurred, rather than by the number of episodes or the duration of neutropenia.

Neutropenia is a clinically relevant consequence of myelosuppressive chemotherapy, and an incidence endpoint gives a direct description of how often a specified severity category was recorded in each study group. The registry also lists related secondary measures, including duration of severe neutropenia, duration of any-grade neutropenia, nadir ANC, time from nadir to a specified ANC threshold, and febrile neutropenia. These measures describe different aspects of neutropenia and should not be treated as interchangeable with the primary incidence outcome.

The primary endpoint was assessed over 21 days. The analysis population excluded participants who missed the blood sampling scheduled at visit 5, the expected time of nadir. That exclusion matters because an unavailable measurement at that point could affect whether the endpoint was observed or classified. The registry record does not report a detailed rule for handling other missing measurements or the precise endpoint-assessment procedure beyond the stated population definition.

7. Results Posted in the Registry

• Empegfilgrastim 6 mg: 65.0% (13/20) versus 85.7% (18/21) on control; risk difference -20.7 percentage points (95% CI -46.4 to 5.0), risk ratio 0.76 (0.53–1.09); unadjusted two-proportion z-test p = 0.123.
• Filgrastim: 61.1% (11/18) versus 85.7% (18/21) on control; risk difference -24.6 percentage points (95% CI -51.6 to 2.4), risk ratio 0.71 (0.47–1.07); unadjusted two-proportion z-test p = 0.079.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Mean Duration of CTCAE Grade 4 Neutropenia

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Empegfilgrastim 6 mg: mean 0.40 versus 0.43 on control; difference -0.03 (95% CI -0.33 to 0.27), standardized effect d = -0.06; z-test p = 0.846.
  • Filgrastim: mean 0.33 versus 0.43 on control; difference -0.10 (95% CI -0.40 to 0.20), standardized effect d = -0.21; z-test p = 0.520.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Empegfilgrastim 6 mg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Filgrastim and the control. The interval gives the range of effects that remain compatible with the data.

The Duration of Any Grade Neutropenia

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Empegfilgrastim 6 mg: mean 1.00 versus 1.86 on control; difference -0.86 (95% CI -1.55 to -0.17), standardized effect d = -0.76; z-test p = 0.014.
  • Filgrastim: mean 0.78 versus 1.86 on control; difference -1.08 (95% CI -1.71 to -0.45), standardized effect d = -1.02; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Empegfilgrastim 6 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Filgrastim than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Duration of Neutropenia From Nadir to ANC < 2,0 x 10^9 Cells/L on the First Cycle of Chemotherapy

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Empegfilgrastim 6 mg: mean 3.80 versus 4.80 on control; difference -1.00 (95% CI -2.14 to 0.14), standardized effect d = -0.54; z-test p = 0.085.
  • Filgrastim: mean 3.00 versus 4.80 on control; difference -1.80 (95% CI -2.86 to -0.74), standardized effect d = -1.08; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Empegfilgrastim 6 mg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Filgrastim than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the posted secondary endpoints, the group means generally place empegfilgrastim 6 mg and filgrastim below empegfilgrastim 3 mg for duration measures, including duration of any-grade neutropenia and duration from nadir to the stated ANC threshold. The Grade 4 duration means are close across groups. The posted nadir ANC and febrile neutropenia measures are named as secondary outcomes, but their numerical results are not reported in the registry record.

This overall pattern provides additional descriptions of neutropenia beyond the primary incidence endpoint, but it does not establish a single consistent effect across all dimensions. Duration and incidence ask different questions: a participant may contribute to an incidence measure without the duration measure conveying the same information, and averages do not show how individual observations are distributed. The secondary outcomes therefore complement rather than replace the primary result.

The pairwise continuous-outcome calculations are unadjusted, and the registry record lists multiple secondary outcomes and comparisons without reporting a multiplicity procedure. When multiple hypotheses are tested, the chance of at least one nominally unusual result can increase. This makes isolated unadjusted p-values less persuasive than results from a prespecified analysis that accounts for the family of questions being examined.

The secondary findings should consequently be treated as exploratory context. Their apparent direction and precision can help identify patterns worth further study, but the record does not establish that these secondary contrasts were prespecified, adequately powered, or adjusted for multiple testing. The absence of reported numerical results for some listed outcomes also limits an across-endpoint assessment.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Mean Duration of CTCAE Grade 4 Neutropenia
• The Duration of Any Grade Neutropenia
• Low Level (Nadir) ANC x 10^9/L
• Duration of Neutropenia From Nadir to ANC < 2,0 x 10^9 Cells/L on the First Cycle of Chemotherapy
• Incidence of Febrile Neutropenia

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary because it records whether each participant experienced CTCAE Grade 3/4 neutropenia during the stated timeframe. For a binary outcome, an incidence or risk is the proportion of participants with the event in a group. A risk difference compares those proportions by subtraction; a negative value in the posted comparisons means the event proportion in the comparison group was lower than in the empegfilgrastim 3 mg reference group. This direction describes the arithmetic contrast, not a causal conclusion on its own.

The recalculated risk difference for empegfilgrastim 6 mg versus empegfilgrastim 3 mg is -0.207, with a 95% confidence interval from -0.464 to 0.05. For filgrastim versus empegfilgrastim 3 mg, it is -0.246, with a 95% confidence interval from -0.516 to 0.024. Both intervals include zero, the value corresponding to no risk difference. Their width indicates that the posted group counts are compatible with a range of possible differences, including values on either side of no difference. The interval is not a probability statement that the true effect has a particular chance of lying inside it.

The recalculated risk ratios and odds ratios are alternative ways to express binary-outcome contrasts. A risk ratio compares the event proportions as a ratio, whereas an odds ratio compares event odds. These measures have different scales and interpretations; neither should be read as an absolute change in risk. The posted recalculations include risk ratios of 0.758 and 0.713, and odds ratios of 0.309 and 0.262, for the respective comparisons. Their confidence intervals are broad and include the null value for each measure. Because the endpoint is common in the posted groups, the odds ratio should not be casually interpreted as though it were a risk ratio.

The reported sponsor analysis uses Fisher Exact across all three groups and reports p <0.05. Fisher Exact is a method for testing association in categorical data that can be useful when group counts are limited. The reported overall test asks whether the distribution of the binary outcome differs across the groups; it does not identify which pair is responsible for that result. The record does not include the sponsor's test statistic, pairwise estimates, or a sponsor-reported confidence interval. The registry's overall result should therefore be kept distinct from the unadjusted pairwise re-calculations.

The p-values in the pairwise recalculations are unadjusted. A p-value describes how compatible the observed data are with a specified null hypothesis under the test's assumptions; it is not the probability that the null hypothesis is true, and it does not quantify the size or practical importance of an effect. The recalculated values are 0.123 for empegfilgrastim 6 mg versus the 3 mg group and 0.079 for filgrastim versus the 3 mg group. They do not replace the sponsor's own overall analysis.

For continuous secondary outcomes, the record gives group means and standard deviations. The recalculated mean difference is the comparison-group mean minus the empegfilgrastim 3 mg mean. Its confidence interval expresses uncertainty around that difference. A standard deviation describes variation among participant measurements within a group; it is not the same quantity as the standard error, which describes uncertainty in an estimated mean. When outcomes are skewed or include many zero values, a mean and standard deviation may not capture the full shape of the data. The record does not report distributions or an alternative model for these outcomes.

General statistical point: over-dispersion matters when count data vary more than a model assumes. Underestimating that variation can make standard errors too small and intervals too narrow. The primary endpoint is posted as participant counts with a binary event, and the registry does not report a count-model analysis for it. The general issue is relevant to interpreting count-based methods in suitable settings, but there is no basis in the record to claim that over-dispersion was assessed or affected this study's analysis.

The analysis population is modified intention-to-treat, with inclusion dependent on receiving at least 1 injection and exclusion for missed blood sampling at visit 5. This is different from an analysis retaining every randomized participant regardless of treatment received or endpoint availability. Excluding participants based on a missing assessment can affect interpretation if the chance of missingness is related to group or outcome. The registry does not report the number excluded for this reason, their group assignments, or a sensitivity analysis addressing missing data.

The planning illustrations use observed effects as inputs, with stated fractions of those effects as alternative targets. They are not evidence about the original trial design or its actual power. No original sample-size rationale or complete analysis plan is reported in the registry record.

11. Confidence Intervals and Precision

The primary risk-difference intervals are broad. For empegfilgrastim 6 mg compared with empegfilgrastim 3 mg, the recalculated estimate is -0.207 and the 95% confidence interval runs from -0.464 to 0.05. For filgrastim compared with empegfilgrastim 3 mg, the estimate is -0.246 and the interval runs from -0.516 to 0.024. Each interval includes zero, so the posted data are compatible with no difference as well as with differences in either direction within the interval.

These intervals convey uncertainty about the pairwise estimates; they are not measures of the range of individual participant outcomes. Their width reflects limited information in the analyzed groups, although the registry record does not report a formal precision target. A point estimate alone can give a misleading impression of certainty, especially when the interval spans a broad range of possible effects.

The registry's Fisher Exact result, p <0.05, is an overall test across three groups. The record does not report a confidence interval for that overall test. The result does not remove the uncertainty in the pairwise recalculations or make their intervals narrower. Since the overall and pairwise analyses address different questions, their p-values and intervals should be read side by side rather than as competing versions of the same estimate.

The secondary continuous-outcome comparisons also have intervals of varying width. For example, the recalculated duration-of-any-grade-neutropenia intervals exclude zero for both comparisons, while the Grade 4 duration intervals include zero. These are unadjusted comparisons, and their precision does not account for the fact that several outcomes and contrasts were examined. Wider intervals indicate less precise estimation; intervals that include zero do not prove there is no difference.

12. 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 participants per arm for the two-group comparisons, not total study enrollment and not total events. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is set at the stated fraction of the observed effect. These are planning assumptions for the illustrations; the trial's own original design assumptions are not reported in the registry record.

The 80% power column gives the estimated participants per arm under those assumptions for a design with an 80% chance of detecting the target effect if that effect is the true one. The 90% power column uses a higher chance of detection and therefore generally calls for more participants per arm. These are design-planning quantities, not guarantees about a future result.

The rows use the full observed effect and smaller fractions of that observed effect. Planning for 75% of the observed effect or 50% of the observed effect requires more participants per arm than planning for 100% of the observed effect, because smaller differences are harder to distinguish from random variation. The figures depend on the observed estimates, which are uncertain in this study; they should not be mistaken for a sample-size justification authored for the trial.

This is not observed power. The illustrations do not tell how likely the completed study was to detect its actual effect after the results were known. They are prospective calculations using stated assumptions and observed effects as reference inputs, and they do not substitute for confidence intervals when assessing uncertainty in the posted findings.

13. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.857; treatment proportion p₁ = 0.650; average p̄ = 0.754.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6094 = 1.1945.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5916 = 0.4979.
4. n = (1.1945 + 0.4979)² / (-0.2071)² = 66.7, rounded up to 67 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
p0 <- 0.857142857142857                          # control proportion
p1 <- 0.65                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1569087)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 67 (80% power), 89 (90% power)
 75% of observed effect: n per arm = 111 (80% power), 148 (90% power)
 50% of observed effect: n per arm = 229 (80% power), 306 (90% power)
power.prop.test: 66.7 
Simulated power at n = 67 per arm: 0.809 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

14. Analyses Reported by the Sponsor

The registry reports the sponsor's primary analysis as a Fisher Exact test across the three groups, with p <0.05. It does not report a sponsor-generated effect estimate or confidence interval for that overall test. The result indicates a reported overall difference in the binary outcome distribution, but it does not specify which individual group comparisons account for it.

The recalculations are unadjusted pairwise risk-difference comparisons against the empegfilgrastim 3 mg group. The empegfilgrastim 6 mg comparison has an estimate of -0.207 and p-value 0.123; the filgrastim comparison has an estimate of -0.246 and p-value 0.079. Their intervals include zero. These pairwise recalculations are not the same test as the sponsor's three-group Fisher Exact analysis, so the different results are not inherently contradictory.

The record marks no discrepancy between the reported analysis and the recalculations. The sponsor's own analysis takes precedence when describing the sponsor-reported result. The recalculated estimates are useful as simple, unadjusted summaries of the posted group counts, but they should not be presented as though the sponsor reported them or as though they replace the reported overall test.

15. Multiplicity, Missing Data and Analysis Populations

The registry reports an overall Fisher Exact test for the primary endpoint and provides unadjusted pairwise recalculations. It does not report whether the sponsor used a multiplicity adjustment for any pairwise testing, nor does it report a hierarchy, gatekeeping procedure, or other method for controlling the family-wise chance of false-positive findings. The record also lists several secondary endpoints, without a reported multiplicity strategy for their analyses.

Multiplicity matters because repeated testing creates more opportunities to obtain a nominally small p-value by chance. This does not mean that any particular result is false; it means that an unadjusted p-value from one comparison should be interpreted in the context of the other analyses. The reported overall test is a distinct, three-group analysis and should not be treated as an adjustment for all pairwise or secondary questions.

The primary population excluded participants who missed blood sampling on visit 5, identified as the expected time of nadir. The registry does not report the number excluded, the distribution of missing measurements among groups, or an imputation or sensitivity analysis. It also does not report how other missing data were handled. If availability of this measurement was associated with group or outcome, the analyzed population could differ in important ways from the randomized population.

The posted analysis included participants who received at least 1 injection of study drug, so it is not described as a full intention-to-treat analysis of all randomized participants. The registry does not report the number of randomized participants excluded for not receiving an injection or provide a complete accounting of participant flow by analysis. These omissions make it difficult to assess the impact of post-randomization exclusions.

Finally, the original sample-size calculation, assumptions about the anticipated endpoint rate or effect, and full statistical analysis plan are not reported in the registry record. The planning illustrations based on observed effects cannot fill that gap. As a result, the prespecification, power rationale, and intended handling of multiple outcomes and missing data remain uncertain.

16. 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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutropenia grade 4 (10.5%).

The adverse-event record lists serious adverse events for 0 of 21 participants in the empegfilgrastim 3 mg group, 0 of 20 in the empegfilgrastim 6 mg group, and 2 of 19 in the filgrastim group. These are serious-event counts among the participants recorded as at risk in each group. The safety denominators are not identical to the primary endpoint analysis denominators, so the safety counts should not be substituted for the primary analysis counts.

The record also lists other adverse events for all participants at risk in each group: 21 of 21, 20 of 20, and 19 of 19, respectively. It identifies neutropenia grade 4 at 10.5% among the top serious adverse-event terms. Death counts are not reported in the registry record.

These summaries describe events recorded in the study; they do not establish comparative safety with precision. The record does not provide a detailed accounting of event timing, duration, severity categories beyond the listed term, or a causal assessment for each event. Group sizes are limited, and the observed counts alone cannot rule out uncommon events or characterize risks beyond the study population and follow-up.

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

The posted results describe a randomized Phase II study comparing two single-dose empegfilgrastim regimens with daily filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer. For the primary endpoint, the observed number of participants with CTCAE Grade 3/4 neutropenia was lower in the empegfilgrastim 6 mg and filgrastim groups than in the empegfilgrastim 3 mg group. The recalculated pairwise intervals are broad and include no difference, while the registry reports an overall Fisher Exact result of p <0.05.

These statements are not contradictory: an overall test across three groups and pairwise estimates against a reference group address different statistical questions. The registry's reported overall result does not, on its own, identify a particular pairwise contrast. The recalculated estimates provide a useful account of the posted counts but are unadjusted and do not replace the sponsor's analysis.

The results do not establish a definitive ranking of the regimens, nor do they show that any regimen works or does not work. The study is limited in size and the primary intervals permit a wide range of possible pairwise differences. The record also does not report the full analysis plan, original sample-size assumptions, or enough information about missing assessments to resolve how these factors may affect interpretation.

The secondary outcomes offer additional descriptive information about the duration and course of neutropenia. They are not substitutes for the primary endpoint and are less conclusive when interpreted as multiple unadjusted comparisons. Safety counts likewise summarize events recorded during the study and cannot rule out uncommon events.

The appropriate statistical reading is therefore bounded: the record documents observed group counts, an overall sponsor-reported test, and imprecise pairwise recalculations. It does not support conclusions beyond those data and the design and analysis details recorded in the registry.

18. Why This Trial Matters Statistically

This trial illustrates why the choice of contrast matters. The sponsor's reported Fisher Exact analysis compares the primary outcome distribution across three groups, while the recalculated risk differences compare each active group separately with empegfilgrastim 3 mg. An overall test can report a difference among groups without identifying which pair differs, and pairwise estimates can remain imprecise even when an overall test is reported as statistically significant.

It also shows the importance of reading effect estimates alongside uncertainty. The observed counts make the group pattern visible, but the confidence intervals include no difference and span substantial ranges. A p-value alone cannot communicate that uncertainty or the size of a possible effect.

The modified intention-to-treat definition is another important statistical feature. Eligibility depended on receiving at least 1 injection, and missing blood sampling at the expected nadir led to exclusion. Post-randomization exclusions and missing outcome data can affect the comparability created by random allocation, but the record does not give enough detail to quantify that impact.

Finally, the study lists several secondary outcomes and comparisons. Without a reported multiplicity strategy, nominal results across those analyses warrant more caution than a single prespecified primary test. Taken together, the record is useful for seeing how design, analysis population, contrast choice, missing data, and multiplicity shape the interpretation of clinical trial results.

19. 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 analysis population was modified intention-to-treat and excluded participants who missed sampling at visit 5, the expected time of nadir. The number of such exclusions and their distribution by group are not reported in the registry record. The record also does not describe other missing-data handling or sensitivity analyses. This limits assessment of whether the analyzed groups remained comparable after randomization.

Although the study is described as randomized, the registry record does not report the sequence-generation method, allocation concealment, or the timing of assignment. It identifies the study as open-label, but does not explain whether outcome assessors were masked. These details would help assess risks of bias; they should not be inferred from the design label alone.

The original sample-size rationale and full statistical analysis plan are not reported. The sponsor's primary result is given as an overall Fisher Exact p-value without a corresponding effect estimate or confidence interval. Pairwise recalculations are unadjusted, and no multiplicity approach is reported for the numerous secondary outcomes. Some listed secondary endpoints have no numerical results in the registry record.

The safety summaries are counts with limited detail, and the serious-event denominators differ from the primary endpoint analysis denominators. The registry does not report death counts, detailed event narratives, or the full context for adverse-event attribution. These issues constrain interpretation of safety and do not permit broad conclusions about uncommon events or applicability outside the study population.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Dose-finding Study of Empegfilgrastim for Neutropenia Prophylaxis in Patients With Breast Cancer — NCT01569087.
• Registry record last updated 2016-12-05; status last verified 2016-10.
• Results first posted 2016-10-24.
• 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.

23. Record Summary

NCT01569087 is a completed, randomized, multicenter, open-label Phase II parallel-group study sponsored by Biocad. It compared single-dose empegfilgrastim 3 mg or 6 mg with daily filgrastim for neutropenia prophylaxis in patients with breast cancer receiving myelosuppressive chemotherapy. Enrollment was 60; the study began in 2012-05 and primary completion was in 2013-01.

The primary endpoint was CTCAE Grade 3/4 neutropenia incidence during 21 days in a modified intention-to-treat population. The sponsor reported an overall Fisher Exact analysis with p <0.05. Unadjusted pairwise recalculations have broad confidence intervals that include no difference. Secondary outcomes describe related neutropenia measures, but not all listed outcomes have numerical results in the registry record, and no multiplicity procedure is reported.