Trial of Pregabalin for Granulocyte Colony-stimulating Factor (GCSF)-Induced Bone Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Pregabalin for Granulocyte Colony-stimulating Factor (GCSF)-Induced Bone Pain (NCT03407430), a randomized phase 2 study. The primary outcome is Number of Patients Who Have an Increase in Pain Score of ≥ 3 From Baseline Through the End of Study Medication in Cycle 1.

2. Clinical Question

The trial addressed prevention of pain associated with pegfilgrastim, a G-CSF used alongside chemotherapy. The registry rationale proposes that pregabalin could affect pain signaling through nerve endings associated with G-CSF receptors. That rationale is a proposed mechanism, not a result of the trial.

The primary outcome focused on a change in pain from each participant’s baseline rather than on pain at a single time point. Pain was rated on a ten-point numerical scale, with 0 meaning no pain and 10 meaning the worst pain imaginable. The endpoint counted participants whose pain score increased by at least 3. The record describes the primary comparison as occurring in cycle 1, before the crossover sequence could supply a within-participant comparison across both treatments.

The record lists breast cancer and lymphoma among the conditions, while its eligibility summary also refers more broadly to non-myeloid hematologic malignancies. It does not report outcome results separately by diagnosis, so the primary counts cannot describe differences between these clinical groups.

3. Trial Design

This was a phase II, randomized, placebo-controlled crossover trial. The registry describes it as single center and states that participants were allocated in a 1:1 ratio. The masking field identifies quadruple masking, while the brief summary calls the study double blind. The identities of the specific masked roles are not reported in the registry record.

Participants were assigned to one of two sequences: pregabalin in cycle 1 followed by placebo in cycle 2, or placebo in cycle 1 followed by pregabalin in cycle 2. The primary endpoint was the cycle 1 comparison, in which the sequence assignment also determined the initial treatment group. The posted primary results list 5 participants in the pregabalin-first group and 3 in the placebo-first group. The registry reports overall enrollment of 11, so the primary-outcome arm counts do not account for every enrolled participant; the reasons and disposition of the remaining participants are not reported in the registry record.

The crossover structure means that participants were intended to receive both study treatments in different cycles. A crossover can support comparisons within the same participant, but interpretation depends on the timing and conduct of the periods, including whether effects carry over. Details such as a washout period, the handling of period effects, and the analysis planned for the crossover data are not reported in the registry record. For the primary outcome, the posted results concern cycle 1, rather than a reported combined analysis of both cycles.

The registry summary says study medication would begin 4 days before pegfilgrastim and continue for 7 additional days starting on the day pegfilgrastim was administered. The arm descriptions state that study medication was given at 75 mg twice a day for 4 days, but do not provide a complete dosing schedule. The primary outcome timeframe is listed as up to 12 weeks. The registry does not explain how that timeframe relates to the medication period or the timing of each pain assessment.

The trial status is terminated. The reason for termination, the timing of the termination decision, and whether it affected planned enrollment or follow-up are not reported in the registry record. No protocol-level sample-size justification or detailed statistical analysis plan is reported.

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: Eleven subjects were screened and successfully consented to this trial. Of these, three subjects either had therapy alteration that led to their exclusion or left without study-related medication, thus 8 subjects were treated.

First Intervention

Washout

Reasons for not completing this period:

Second Intervention

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients Who Have an Increase in Pain Score of ≥ 3 From Baseline Through the End of Study Medication in Cycle 1, measured over Up to 12 weeks.

The primary endpoint counted participants whose pain score increased by at least 3 points from baseline through the end of study medication in cycle 1. Pain was rated on a numerical scale from 0, no pain, to 10, the worst pain imaginable. The endpoint therefore converted repeated pain ratings into a participant-level event: either the specified increase occurred or it did not.

A change-from-baseline endpoint can make a treatment comparison more focused on worsening relative to a participant’s own starting pain level. Using a threshold also gives the outcome a clinically interpretable form: the analysis asks how many participants crossed a prespecified amount of worsening, rather than comparing only average scores. These are general properties of threshold-based change outcomes, not evidence that the threshold was validated for this trial.

The registry’s primary outcome title and description concern the number or proportion of participants experiencing the increase. The posted results give counts of 0 in the pregabalin-first group, with 5 participants, and 0 in the placebo-first group, with 3 participants. No treatment-effect estimate, confidence interval, or statistical test is reported. The counts therefore do not establish whether the groups differed in the broader population.

The endpoint is not the only pain-related measure listed. Secondary outcomes include bone or joint pain, severe pain, maximum change in pain score, neuropathic pain, and use of breakthrough analgesics. Those measures could describe different aspects of the pain experience, but their results are not reported in the registry record. The primary outcome also does not, by itself, describe pain severity among participants who did not cross the threshold.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary endpoint count? A binary endpoint classifies each participant according to whether a defined event occurred. For this trial, the event was an increase in pain score of at least 3 from baseline by the end of study medication in cycle 1. The posted results report the number of participants with the event and the number listed in each group. This is different from reporting the average pain score or the average change in score.

Binary outcomes can be summarized as counts, proportions, or contrasts between proportions. A contrast expresses the difference or relative relationship between groups; a confidence interval describes the range of values compatible with the data under the analysis model. These are general statistical concepts. The registry record reports counts for the primary endpoint but does not report a contrast, confidence interval, or p-value. No additional estimate should be inferred from the counts alone.

Why does the small count matter? The primary result lists 5 participants in the pregabalin-first group and 3 in the placebo-first group, with 0 events in both. When groups and event counts are small, estimates from a binary outcome can be imprecise, and conventional approximations may perform poorly. A zero count is still an observation, but it does not imply that the underlying event probability is exactly zero. A confidence interval or suitable model would be needed to characterize uncertainty, and neither is reported.

What does randomization contribute? Random assignment is intended to make treatment groups comparable, on average, with respect to factors known and unknown at the time of assignment. It does not ensure exact balance in a small trial. The registry identifies randomization and a 1:1 allocation ratio, but does not report the sequence-generation method, concealment procedures, or baseline characteristics by assigned sequence. The degree of comparability in this enrolled sample cannot therefore be assessed from the registry record alone.

How does the crossover design affect interpretation? In a crossover design, participants receive more than one treatment in different periods, allowing comparisons that may account for stable differences between participants. Such analyses must consider period effects and the possibility that an earlier treatment affects outcomes in a later period. The registry describes two treatment sequences, but the primary result is for cycle 1. It does not report a crossover model, within-participant estimate, period-effect assessment, or carryover assessment. The primary result should not be treated as if those analyses had been performed.

What is the role of a confidence interval? In general, a confidence interval communicates statistical precision by giving a range around an estimate. A narrow interval indicates greater precision under the assumptions of the method; a wide interval indicates less precision. It does not guarantee that the true effect lies in the interval for a particular study. Since no interval is reported for this endpoint, the precision of any treatment contrast is not quantified in the registry record.

How should p-values be understood? In general, a p-value measures how incompatible the observed data are with a specified null model, subject to that model’s assumptions. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. No p-value or other inferential test is reported for the primary outcome. The absence of a posted test means the registry result is descriptive rather than a reported formal test of a treatment difference.

What can planning calculations say? Sample-size calculations are planning illustrations based on assumptions about an effect, variability or event rate, allocation, and analysis method. They do not describe the observed trial result and are not observed power. The registry’s planning description refers to a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a fraction of the observed effect. The resulting planning values and the fractions are not reported in the registry record. The registry also does not report its own sample-size justification, so the planning description should not be read as the trial’s original design calculation.

What does over-dispersion mean in general? Over-dispersion occurs when observed variability is greater than a statistical model assumes. For counts, this can make standard errors too small and intervals too narrow if the model does not account for the extra variability. It is a general issue in some count-data analyses. The primary endpoint is reported as a binary participant count, and the registry does not report a model or over-dispersion assessment. No claim about over-dispersion in this trial is warranted.

What can be inferred from the posted analyses? The registry lists 0 primary events in each of the two groups, but reports 0 analyses. It does not provide an adjusted or unadjusted treatment estimate, model specification, missing-data method, or analysis population definition. There is consequently no reported inferential analysis to interpret or validate against the counts. Any statistical description should remain at the level of the posted participants and events.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("First Intervention = Pregabalin", "First Intervention = Placebo")
n      <- c(5, 3)
events <- c(0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  First Intervention = Pregabalin  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  First Intervention = Placebo  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 secondary outcomes in addition to the primary outcome. These cover pain across both cycles, bone or joint pain, breakthrough analgesic use, severe pain, maximum pain change, neuropathic pain, and adverse events. No analyses are posted for these outcomes. The record does not report a multiplicity strategy, such as a hierarchy of tests or an adjustment for multiple comparisons. Without that information, the role of the secondary outcomes in any confirmatory testing cannot be determined.

Multiplicity matters when many outcomes or comparisons are examined because the chance of at least one apparently notable finding can increase. This is a general statistical concern, not a statement that a false-positive finding occurred in this trial. Since no secondary results or inferential tests are reported, the registry does not allow assessment of how multiplicity was handled in practice.

The overall enrollment is 11, whereas the primary outcome lists 5 participants in the pregabalin-first group and 3 in the placebo-first group. The record does not explain the remaining enrollment, indicate the number of participants completing each cycle, or describe exclusions from the primary outcome. Missing outcome data, withdrawals, and reasons for non-inclusion are not reported in the registry record. It is also not reported whether any missing values were imputed or otherwise handled.

The analysis population is not defined. In particular, the record does not say whether the primary comparison used all randomized participants, only participants who started study medication, or participants with available outcome data. The method used to analyze the crossover periods is also not reported. These omissions limit assessment of attrition, adherence to the assigned sequence, and the possibility that the analyzed participants differed from those enrolled.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports no serious adverse events and no deaths in any of the listed treatment-period groups. The groups are shown as first intervention with pregabalin, second intervention with placebo, first intervention with placebo, and second intervention with pregabalin. The corresponding numbers at risk are 5, 4, 3, and 3, respectively; the serious adverse-event count is 0 in each group, as is the death count.

The record also reports other adverse events in all participants listed at risk in each group: 5 of 5, 4 of 4, 3 of 3, and 3 of 3. The terms or severity details for these other events are not reported in the registry record. These counts do not identify the nature, timing, or relationship of events to study medication.

Because this is a crossover study, participants may contribute observations in more than one treatment period. The period-specific group counts should not be added to create a count of unique participants. Nor do zero serious events establish that serious harms cannot occur; the numbers observed are limited, and no comparative safety estimate or uncertainty interval is reported. These figures describe only the adverse-event information posted in the registry.

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

The primary outcome offers a direct description of the cycle 1 observations: the registry records no participants meeting the specified pain-increase threshold in either initial treatment group. It is useful to distinguish this descriptive result from a claim about the treatment effect. The record does not report an estimate or uncertainty interval comparing pregabalin with placebo, and the small number of participants with primary outcome counts limits how much can be learned from the absence of recorded events.

The result does not show that pain never increased among participants, because the endpoint counted only increases of at least 3 from baseline. Smaller increases, pain at other times, and other aspects of pain are not captured by that count. Nor does the primary result describe the secondary pain outcomes, which are listed but have no posted analyses.

The crossover plan intended participants to receive pregabalin and placebo in separate cycles. The reported primary outcome is limited to cycle 1, so it is not a reported estimate based on each participant’s experience under both treatments. Details required to interpret a complete crossover analysis, including period effects and carryover, are not reported in the registry record.

The trial’s terminated status is a fact about the record, but the reason is not reported. It cannot be used alone to infer a disappointing result, a safety concern, or a problem with recruitment. Similarly, the reported absence of serious adverse events and deaths is a description of the posted counts, not evidence that the safety profiles are equivalent or that uncommon events are excluded.

In short, the registry supports a limited account of observed primary events and safety counts. It does not provide the inferential analysis, missing-data accounting, or detail on trial conduct needed to make a precise treatment-effect claim. General conclusions about the eligible population would require evidence beyond these posted counts.

14. Why This Trial Matters Statistically

This trial illustrates why an observed count and a treatment comparison are not the same thing. The primary endpoint is clearly defined as crossing a pain-change threshold, and the registry records the event count in each initial treatment group. Yet the counts alone do not quantify the size or precision of a treatment contrast. A statistical result needs both an estimate and a way to understand its uncertainty, especially when few participants contribute to the comparison.

It also highlights the interpretive demands of crossover studies. A crossover design can use within-participant information, but its advantages depend on appropriate analysis of treatment sequence and period. Here, the posted primary result concerns cycle 1, and the registry does not report an analysis combining both cycles. Recognizing which part of a design is represented by the result prevents a cycle 1 comparison from being mistaken for a complete crossover estimate.

The gap between overall enrollment and the primary-outcome group counts is another important statistical issue. Without participant flow and analysis-population details, readers cannot assess whether the posted outcome includes all randomized participants or how incomplete observations were handled. Transparent reporting of denominators and missing outcomes is essential for evaluating potential bias.

Finally, the registry lists several secondary outcomes and provides adverse-event counts, but does not post inferential analyses or detailed event descriptions. This distinction matters: a registered outcome is not the same as a reported result, and a descriptive safety count is not a comparative safety analysis. Careful interpretation therefore depends not only on the design and outcome definitions, but also on what information is actually reported.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The small primary-outcome groups are a central limitation of the posted evidence. The registry reports 5 participants in the pregabalin-first group and 3 in the placebo-first group, with no primary events in either group. These counts provide little information about precision, and no confidence interval or statistical test is reported. Overall enrollment was 11, but the record does not explain why the primary-outcome counts cover fewer participants.

The terminated status limits interpretation of trial completion, but the reason for termination and its effect on follow-up are not reported. The registry does not provide participant flow, outcomes by cycle completion, adherence information, or reasons for withdrawal or non-inclusion. The resulting risk of bias from missing outcomes cannot be assessed.

Although the trial is described as a crossover, the posted primary result is a cycle 1 comparison. There is no reported within-participant treatment estimate or assessment of period and carryover effects. The record does not provide the crossover analysis plan, washout details, or enough information to assess whether both periods were completed as intended.

The record also lacks baseline characteristics by randomized sequence, a detailed randomization procedure, a definition of the analysis population, and a reported model. It lists secondary outcomes without posting their analyses and does not state how multiplicity was addressed. Safety information is limited to counts; the terms of other adverse events and treatment relationships are not reported. These gaps constrain both statistical interpretation and assessment of the trial’s conduct.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trial of Pregabalin for Granulocyte Colony-stimulating Factor (GCSF)-Induced Bone Pain — NCT03407430.
• Registry record last updated 2018-06-26; status last verified 2018-06.
• Results first posted 2018-06-26.
• 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.

19. Record Summary

The registry record describes a phase II, randomized, placebo-controlled crossover trial of pregabalin for pegfilgrastim-induced bone pain in people receiving chemotherapy for breast cancer or a non-myeloid hematologic malignancy. Participants were assigned to receive pregabalin then placebo, or placebo then pregabalin. The primary question concerned an increase in pain score of at least 3 from baseline through the end of study medication in cycle 1.

The record lists overall enrollment of 11 and primary outcome counts of 0 events among 5 participants in the pregabalin-first group and 0 among 3 in the placebo-first group. It reports no primary inferential analysis, confidence interval, or p-value. Seven secondary outcomes are listed without posted analyses. Serious adverse events and deaths are recorded as 0 in the listed groups; other adverse events are recorded for all participants listed at risk, without event terms.

The study status is terminated. Its reason, participant disposition, missing-data handling, analysis population, sample-size justification, and detailed statistical plan are not reported in the registry record.