Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy (NCT02872103), a randomized phase 3 study. The primary outcome is The Duration in Days of Grade 4 (Severe) Neutropenia Observed in Chemotherapy Cycle 1 in Comparison to Placebo.

2. Clinical Question

The clinical question concerns whether the duration of Grade 4, or severe, neutropenia during the first chemotherapy cycle differed between women assigned F-627 and women assigned placebo. Severe neutropenia is defined in the record by an absolute neutrophil count (ANC) below 0.5 × 10^9/L. The outcome is measured in days, with a shorter duration representing fewer days meeting that laboratory threshold.

The study enrolled women with stage II-IV breast cancer receiving chemotherapy. The intervention was F-627, a 20 mg fixed dose given on Day 2 of each of 4 chemotherapy cycles. The comparison group received placebo on Day 2 of the first cycle, followed by F-627 on Day 2 of each of the following 3 cycles. Thus, the primary comparison is specifically between F-627 and placebo during the first cycle; later cycles do not maintain a placebo comparison.

The posted first-cycle means were 1.3 days for F-627 and 3.9 days for placebo. The estimated mean difference, defined as F-627 minus placebo, was -2.6 days. These are group-level results for the registered endpoint; they do not describe how every participant's neutropenia changed or establish the result for other outcomes.

3. Trial Design

This completed study is registered as a phase 3, randomized, parallel-group, multicentre, double-blind, placebo-controlled trial. The record also lists quadruple masking. It does not identify which roles were masked, so the meaning of that masking designation in practice is not reported in the registry record. The study was sponsored by EVIVE Biotechnology.

The registry describes random assignment at a 2:1 ratio. The posted primary outcome groups include 83 participants assigned to F-627 and 39 assigned to placebo, for an enrollment of 122. The primary endpoint is the duration of Grade 4 neutropenia in the first of 4 chemotherapy cycles, described as a 21 Day cycle and an average of 3 weeks. Its measure is a mean in days with a standard deviation.

The intervention schedule is important to interpreting the comparison. The F-627 group received F-627 on Day 2 of each of 4 cycles. The group named Placebo received placebo during the first cycle and F-627 during the following 3 cycles. The registered primary comparison is therefore the first-cycle contrast, when the assigned groups received F-627 or placebo. The later-cycle schedule does not provide a continuing placebo comparison.

The registry lists a start date of 2016-08, primary completion on 2017-12-20, and status COMPLETED. It describes monitoring ANC daily after chemotherapy until the value exceeded 2.0x10^9/L, then every three days until the next cycle. The posted outcome summaries include the first-cycle group means and standard deviations, a mean difference, a confidence interval, and a p-value. Details such as the participating centres, concealment procedure, exact analysis population, and trial-specific sample-size justification are not reported in the registry record.

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.

Cycle 1

Cycle 2-4

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 The Duration in Days of Grade 4 (Severe) Neutropenia Observed in Chemotherapy Cycle 1 in Comparison to Placebo, measured over The first of 4, 21 Day Chemotherapy Cycles, an average of 3 weeks.

The primary endpoint is the duration, in days, of Grade 4 neutropenia during the first chemotherapy cycle. Grade 4 neutropenia is defined as an ANC below 0.5 × 10^9/L. According to the outcome description, ANC was monitored after chemotherapy and the duration was based on the time spent at this severe-neutropenia threshold. Monitoring was described as daily until ANC exceeded 2.0x10^9/L, then every three days until the next chemotherapy cycle.

Duration is a continuous measure: it records how long the threshold-defined state persisted rather than simply whether a participant experienced it. The primary summary is the group mean number of days, accompanied by a standard deviation. Comparing means describes the difference in average duration between the groups, while the standard deviation describes variation among participants within each group.

This endpoint is used to assess a specific laboratory-defined aspect of neutropenia during the cycle in which the randomized groups received F-627 or placebo. It is distinct from the listed secondary outcomes, which include neutropenia duration in later cycles, severity grades, febrile neutropenia, ANC recovery, ANC nadir, infections, and use of antibiotics and pain medications. Results for those other outcomes are not included in the posted primary comparison summarized in the record. The endpoint is a clinical-trial measure, not a complete description of participants' health or of every possible effect of treatment.

7. Results Posted in the Registry

• F-627: mean 1.30 versus 3.90 on control; difference -2.60 (95% CI -3.09 to -2.11), standardized effect d = -2.11; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

For a continuous endpoint, a group mean is the arithmetic average of participant-level measurements in that group. Here, the measurement is duration in days. The posted mean of 1.3 days for F-627 and 3.9 days for placebo provides a concise description of the first-cycle group results. The mean difference of -2.6 days expresses the contrast as F-627 minus placebo. Its sign depends on that ordering: a negative value means the F-627 group mean is lower than the placebo group mean.

What does the standard deviation describe?

A standard deviation describes how dispersed individual measurements are around their group mean. The posted standard deviations are 1.17 days for F-627 and 1.35 days for placebo. They are not standard errors and they are not confidence limits. Standard deviations describe variability among participants; standard errors describe uncertainty in an estimated quantity, such as a group mean or a difference in means. The registry record does not explain how the outcome distribution was assessed or whether any transformation or alternative summary was considered.

What does the confidence interval add?

A confidence interval expresses estimation uncertainty around the mean difference. The posted 95% interval extends from -3.093 to -2.107 days. In general, a confidence interval is constructed by a procedure that, over repeated applications under its assumptions, would cover the underlying quantity at its stated confidence level. It is not a range containing a specified fraction of individual participants' measurements, and it is not a probability statement about the true value after observing the data. The record does not report the formula or model used to obtain this interval.

How should the p-value be read?

The posted unadjusted p-value is <0.001. In general, a p-value measures how compatible the observed data, or more extreme data, are with a stated reference hypothesis under the assumptions of the analysis. It is not the probability that the reference hypothesis is true, and a small p-value does not by itself indicate the size, precision, or importance of an effect. The record does not report the named test or model behind this p-value, so the posted value can be described but its exact calculation cannot be independently reconstructed from the registry record.

Why can variation affect the analysis?

In general, the variability of measurements affects the uncertainty of a group comparison. Greater variation can make a mean difference harder to estimate precisely when other design features are held constant. The posted standard deviations offer information about the observed spread, but the registry record does not describe checks of distributional assumptions or whether the endpoint included unusual values. For count data or other outcomes with variability greater than a simple model expects, over-dispersion can make conventional uncertainty estimates too small; this general concern is not a claim that over-dispersion occurred for this continuous endpoint.

What is and is not established by randomization?

In general, random assignment supports a fair comparison by reducing systematic differences in expectation between assigned groups. It does not guarantee that every characteristic is balanced in a particular enrolled sample, and it does not resolve missing-outcome or analysis choices. The record states that assignment was randomized, but details of sequence generation, concealment, and the analysis population are not reported in the registry record. The first-cycle comparison matches the randomized treatment contrast described in the outcome: F-627 versus placebo.

How do secondary outcomes fit the analysis?

The record lists 8 secondary outcomes and 9 outcome measures. They cover several related but distinct measures, including durations across cycles, neutropenia grades, febrile neutropenia, ANC recovery and nadir, infections, and medication use. Multiple outcomes create a general multiplicity concern: when many hypotheses are examined, the chance of at least one apparently notable result can increase if no adjustment or prespecified hierarchy is used. The registry record does not report a multiplicity adjustment, a testing hierarchy, or a statistical analysis plan. The primary p-value is identified as unadjusted; it should not be treated as an adjusted result for a family of outcomes.

These method descriptions distinguish what is reported from general statistical interpretation. The posted mean, standard deviation, mean difference, confidence interval, and p-value can be described directly. The precise model, inferential procedure, missing-data method, and prespecified analysis choices are not reported in the registry record. No recalculated result is needed because the discrepancy flag is false.

10. Confidence Intervals and Precision

The estimated first-cycle mean difference is -2.6 days, and its posted 95% confidence interval is -3.093 to -2.107 days. The interval is relatively concentrated around the point estimate in the units of the outcome, days. It describes uncertainty in the estimated difference between group means under the interval's statistical assumptions; it does not show the distribution of individual durations or guarantee that the underlying difference lies within these endpoints.

The estimate is based on 83 participants in the F-627 group and 39 in the placebo group. The posted standard deviations are 1.17 and 1.35 days, respectively. Those values describe observed variation within each group, while the confidence interval describes uncertainty in the estimated between-group difference. These are related but different features of the data.

The posted interval lies on the negative side of zero, consistent with the negative point estimate and the reported unadjusted p-value of <0.001. This is a statement about the registered first-cycle mean-duration contrast, not about all outcomes or all cycles. Precision in this estimate does not resolve questions about missing outcome data, the analysis population, multiplicity, or the exact method used to form the interval; those details are not reported in the registry record.

Confidence intervals are generally more informative than a significance label alone because they present a range of effect sizes compatible with the data and method. Still, interpretation depends on the quality of the measurements and the appropriateness of the analysis. The interval should be read in days and in the context of the first-cycle randomized comparison. It does not establish what differences would be seen under the later-cycle schedule, when the placebo group received F-627.

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 sample-size display gives planning illustrations in participants per arm, not a count of observed participants and not a recommended enrollment for this trial. Its calculations use the observed mean difference as the reference effect and then consider planning for 100%, 75%, and 50% of that observed effect. For each assumed effect, the display gives separate figures for 80% power and 90% power. These percentages describe the chance, under the planning assumptions, of detecting the chosen effect at the stated significance level if that effect were the true one.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The sample-size figures are participants per arm; they are not total events. The record notes that time-to-event calculations use the total number of events, but this primary endpoint is continuous, and the displayed planning figures are per-arm participant counts.

For planning for 100% of the observed effect, the illustrations are 4 participants per arm for 80% power and 5 participants per arm for 90% power. For planning for 75% of the observed effect, they are 7 and 9 participants per arm. For planning for 50% of the observed effect, they are 15 and 19 participants per arm. The curve visualizes the relationship between the assumed effect and the planning requirement: smaller effects need more participants to detect under the same assumptions. The higher power target also calls for a larger planned sample at a given effect assumption.

These figures are not observed power. They are calculations based on the observed effect for illustration, not the original design rationale. The trial's own sample-size justification and original design assumptions are not reported in the registry record. The calculations also assume equal allocation, whereas the trial description states a 2:1 randomization ratio; therefore, the display should not be read as a reconstruction of the trial's actual design or as a report of its planned enrollment.

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 = -2.600; pooled standard deviation σ = 1.230.
2. n = 2 × (1.96 + 0.842)² × 1.230² / -2.600² = 3.5, rounded up to 4 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 <- -2.6                      # observed difference in means
sigma <- 1.22985364982993                     # 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(2872103)
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 = 4 (80% power), 5 (90% power)
 75% of observed effect: n per arm = 7 (80% power), 9 (90% power)
 50% of observed effect: n per arm = 15 (80% power), 19 (90% power)
power.t.test: 4.7 
Simulated power at n = 4 per arm: 0.701 (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. Multiplicity, Missing Data and Analysis Populations

The record lists 8 secondary outcomes alongside the primary outcome. These cover multiple measures of neutropenia, febrile neutropenia, ANC recovery and nadir, infections, and medication use. Examining multiple endpoints raises a general multiplicity issue: without a prespecified strategy, the chance of obtaining at least one small p-value can increase as more hypotheses are tested. The registry record does not report a testing hierarchy, multiplicity adjustment, or analysis plan. The posted primary p-value is unadjusted, so it should be interpreted as an unadjusted result rather than as evidence that accounts for all outcomes.

Missing-data handling is another important part of interpreting a clinical-trial estimate. The registry record does not report how missing ANC measurements or incomplete outcome records were handled, whether any participants lacked endpoint data, or whether sensitivity analyses were conducted. The outcome description says ANC was monitored on a schedule, but it does not establish that every scheduled measurement was available for every participant.

The analysis population is also not reported in the registry record. In general, trial results may be analyzed according to assigned group or according to treatment received, among other approaches. The record identifies randomized groups and provides arm-level sample sizes for the posted endpoint, but it does not state whether all randomized participants were included in the endpoint analysis or how deviations from assigned treatment were treated.

Details of randomization sequence generation and allocation concealment are not reported in the registry record. The registry labels the trial randomized and lists quadruple masking, while the study summary describes it as double-blind. Which participants, clinicians, assessors, or other roles were masked is not reported. The record also does not report whether interim analyses were planned or conducted, whether the primary analysis was prespecified in a separate statistical plan, or how protocol deviations were addressed. These absences do not negate the posted outcome values, but they limit assessment of the full analysis process and the degree to which the posted comparison follows a prespecified approach.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (28.2%), diarrhea (2.6%), pneumonia (2.6%), tumor hemorrhage (1.2%).

The registry lists serious adverse events for the first cycle and for the full treatment schedules. During Cycle 1, serious adverse events affected 4 of 83 participants in the F-627 group and 10 of 39 in the placebo group. Across all 4 cycles of F-627, 4 of 83 participants were reported with serious adverse events. In the group receiving placebo during Cycle 1 and F-627 during Cycles 2-4, 11 of 39 participants were reported with serious adverse events. Deaths were listed as 0 in each of the four groups.

The record also gives the most frequently listed serious adverse-event terms and their percentages: Febrile Neutropenia, 28.2%; Diarrhea, 2.6%; Pneumonia, 2.6%; and Tumor hemorrhage, 1.2%. The record does not further specify the denominator or analysis period for these term percentages in the information presented. They should therefore be read as registry-listed percentages, not as rates recalculated from the group counts.

These figures are descriptive counts and do not by themselves establish that a treatment caused an event or explain differences in exposure across the schedules. The groups had different treatment sequences after the first cycle, so the all-cycle groups are not a continued placebo-versus-F-627 comparison.

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

The posted result describes a difference in the average duration of Grade 4 neutropenia during the first chemotherapy cycle. The F-627 group mean was 1.3 days and the placebo group mean was 3.9 days; the estimated mean difference was -2.6 days, with a 95% confidence interval from -3.093 to -2.107 days and an unadjusted p-value of <0.001. In statistical terms, the point estimate and interval indicate a lower group mean duration in the F-627 arm for this registered outcome during that cycle.

This result does not describe every participant's experience. Group averages can coexist with individual values that differ substantially, and the standard deviations show there was variation within both groups. Nor does the primary result answer whether other outcomes differed. The record lists secondary measures such as febrile neutropenia, infections, ANC recovery, and medication use, but those results are not part of the primary comparison summarized in the record.

The comparison is confined to the first cycle, when one randomized group received F-627 and the other received placebo. The placebo group then received F-627 in the subsequent 3 cycles. Consequently, the result does not estimate a sustained contrast between F-627 and placebo over all cycles. It also does not establish results for people outside the registered population of women with stage II-IV breast cancer receiving chemotherapy.

Statistical significance is not the same as clinical importance. The registry result gives an estimate in days and a confidence interval, but the record does not provide a threshold for judging what size of difference is clinically meaningful. It also does not report sufficient detail about the analysis population, missing data, or the exact inferential method to resolve those aspects of interpretation. The result is a statistical description of the posted first-cycle data, not medical advice or a complete assessment of benefits and risks.

16. Why This Trial Matters Statistically

This trial offers a clear example of why the exact timing and treatment sequence matter when interpreting a randomized comparison. During the first chemotherapy cycle, assignment separated F-627 from placebo. After that cycle, the group initially assigned placebo switched to F-627. The first-cycle mean difference therefore addresses a defined randomized contrast, while the later schedule cannot be interpreted as continued placebo control.

The endpoint also illustrates the difference between a binary and a continuous outcome. The primary measure is not simply whether severe neutropenia occurred; it is the duration in days for which the ANC met the Grade 4 threshold. Reporting group means and standard deviations gives information about average duration and participant-to-participant variability, while the confidence interval characterizes uncertainty in the mean difference.

There is also a useful distinction between an observed result and a planning calculation. The sample-size illustrations use the observed effect as an input and consider smaller assumed effects. They are not the trial's original design justification, and the record does not report that justification. This distinction prevents a retrospective calculation from being mistaken for evidence that the study was prospectively designed around those sample sizes.

Finally, the registry record illustrates the limits of a numerical result without complete analysis documentation. The primary estimate and interval are posted, but details of the model, missing-data procedures, analysis population, and multiplicity strategy are not reported in the registry record. Statistical interpretation therefore requires both attention to the numerical estimate and restraint about methods or conclusions that the record does not establish.

17. 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 trial-specific limitation in interpreting the primary result is that the registry record does not describe the exact statistical model or test used to produce the confidence interval and p-value. It also does not report the primary analysis population, missing-data procedures, sensitivity analyses, or checks of distributional assumptions. These omissions prevent a full appraisal of the analysis from the record alone.

The treatment schedule limits the scope of the randomized placebo comparison. The primary endpoint is measured in Cycle 1, when the groups received F-627 or placebo, but participants assigned placebo received F-627 in Cycles 2-4. Any across-cycle interpretation must account for this change in treatment. The primary first-cycle estimate should not be generalized as a comparison of continued treatment against continued placebo.

The masking description is not fully resolved in the registry record: the study is described as double-blind in the summary and quadruple-masked in the design listing, without specifying the roles masked. Details of sequence generation and allocation concealment are also not reported in the registry record. The record does not describe the number of centres or the extent of protocol adherence.

The primary outcome is one of several registered measures, but a multiplicity strategy is not reported. The record lists 8 secondary outcomes and identifies the primary p-value as unadjusted. The clinical importance threshold for a difference in duration is not reported in the registry record, so statistical precision alone cannot determine its practical importance. These are limitations of what can be concluded from the registry information, not claims that the underlying trial necessarily lacked these procedures.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy — NCT02872103.
• Registry record last updated 2021-05-05; status last verified 2021-04.
• Results first posted 2019-03-26.
• 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.

21. Record Summary

NCT02872103 is a completed phase 3, randomized, parallel, placebo-controlled trial sponsored by EVIVE Biotechnology. It enrolled 122 women with breast cancer receiving myelotoxic chemotherapy. The primary endpoint was the duration of Grade 4 neutropenia during the first chemotherapy cycle.

For the primary comparison, the F-627 group included 83 participants and had a mean duration of 1.3 days; the placebo group included 39 participants and had a mean duration of 3.9 days. The mean difference was -2.6 days, with a 95% confidence interval of -3.093 to -2.107 days and an unadjusted p-value of <0.001. The placebo group received F-627 during the following 3 cycles, so this estimate concerns the first-cycle comparison.

The record lists 8 secondary outcomes. Details of the original sample-size justification, missing-data handling, analysis population, and statistical analysis plan are not reported in the registry record.