Pharmacodynamic Study of Cilostazol in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacodynamic Study of Cilostazol in Healthy Volunteers (NCT02554721), a randomized phase 1 study. The primary outcome is Ex-vivo Inhibition Of Platelet Aggregation (IPA).

2. Clinical Question

3. Trial Design

This is a completed Phase 1 randomized, unmasked, parallel study of cilostazol and other antiplatelet agents in healthy volunteers. The registry lists enrollment of 77. The study’s stated objective was to investigate the effects of cilostazol, acetylsalicylic acid, and clopidogrel alone, as well as cilostazol combinations with each reference medication, on ex-vivo platelet-function testing. Skin bleeding time is listed as a secondary outcome.

The registry describes four groups. One group is identified as CYP2C19 wild type and has periods of cilostazol, washout, acetylsalicylic acid, and the combination of cilostazol with acetylsalicylic acid. Two further groups, one wild type and one heterozygous (*1/*2), are described for clopidogrel and cilostazol periods. A fourth group is identified as homozygous (*2/*2) and is also described for the clopidogrel regimens. The clopidogrel group descriptions specify a 1-week clopidogrel period and a 1-week combination period, following the cilostazol and washout periods. The registry’s description of the acetylsalicylic acid combination period is truncated.

Although the overall design is labeled parallel, the primary-outcome population definition focuses on subjects who completed both the reference-medication-alone period and the combination period. The record does not report the operational details of treatment assignment, the allocation procedure, or the rationale for the genotype groups. It also does not report a protocol-level explanation of how the described treatment periods relate to the parallel-design label. The study start is listed as 2015-08, primary completion as 2018-03-30, and status as completed.

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: A total of 77 healthy adult male participants were enrolled. Following administration of cilostazol in Period A and wash-out in Period B, participants were stratified according to CYP2C19 genotype and assigned to Groups 1-4 for further treatment in Periods C and D. Two participants who received cilostazol in Period A were not assigned to a group.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set: All subjects who completed both periods of treatment with reference medication alone (Period C) and treatment with reference medication and cilostazol (Period D)

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.

Population: Safety Analysis Set: All subjects who received at least 1 dose of trial medication

6. Primary Endpoint

The registry lists the primary outcome as Ex-vivo Inhibition Of Platelet Aggregation (IPA), measured over Baseline, Visit 5 (Day 22-29).

The primary endpoint is ex-vivo inhibition of platelet aggregation, reported as a ratio. Platelet-rich plasma was stimulated with low-level adenosine diphosphate (ADP) or arachidonic acid (AA), and light transmission aggregometry was used to measure residual aggregation. Residual aggregation is described as the percentage of aggregation 5 minutes after the stimulating agent was added. The registry specifies ADP at 5 micromolar and AA at 500 milligrams/liter.

The endpoint is expressed as a geometric mean ratio comparing the combination of cilostazol with the reference medication against the reference medication alone. The registry describes 95% confidence intervals for these ratios. A ratio expresses the relative value of one treatment condition to another; the direction and magnitude of an estimate would be needed to describe the observed contrast. The registry record does not report numerical ratios or confidence intervals, so the size and precision of the primary-outcome findings cannot be assessed from the posted results.

Ex-vivo platelet testing measures a laboratory response in collected platelet-rich plasma rather than a clinical event. It is used in this study to characterize platelet aggregation under specified stimulation conditions. Such a measurement addresses the laboratory endpoint stated in the protocol record; it does not by itself establish what happened to bleeding or other clinical outcomes. Skin bleeding time is listed separately as a secondary outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods can be understood by separating the endpoint, the comparison, and the population included in the analysis. The endpoint is ex-vivo inhibition of platelet aggregation. The comparison is the combination of cilostazol with a reference medication versus that reference medication alone. The primary-outcome population includes subjects who completed both treatment periods. The registry record supplies these definitions but does not report the numerical results or the model used to analyze them.

What a geometric mean ratio represents

A ratio compares the value in one condition with the value in another. In this study, the stated ratio places the combination condition in the numerator and the reference-medication-alone condition in the denominator. A ratio is useful for describing relative rather than absolute differences, particularly when outcomes are naturally interpreted proportionally or have a skewed distribution. A geometric mean summarizes values on a multiplicative scale: conceptually, the data are considered on a logarithmic scale and then expressed back as a ratio. This general description does not establish that any particular statistical model or transformation was used in the trial; that method is not reported in the registry record.

Why the confidence interval matters

A confidence interval communicates the uncertainty around an estimated effect. Its endpoints indicate a range of values compatible with the data under the analysis assumptions. A narrower interval indicates greater precision than a wider interval, while the location of the interval helps readers assess the direction and scale of the estimate. The registry specifies 95% confidence intervals for the reported geometric mean ratios, but numerical interval endpoints are not reported in the registry record. Therefore, neither the estimates’ precision nor their relation to a ratio of 1 can be evaluated from the posted results. A confidence interval is not a guarantee that the true effect lies inside its endpoints, and its interpretation depends on the design and analysis assumptions.

Laboratory measurement and endpoint structure

Light transmission aggregometry was used to measure residual aggregation in citrated platelet-rich plasma after stimulation with ADP or AA. The residual aggregation measure is described as the percentage of aggregation 5 minutes after adding the stimulus. The endpoint description specifies both stimulation conditions and reports the combination-to-reference geometric mean ratios for inhibition of platelet aggregation. The registry does not state whether the two stimulation conditions were analyzed as separate endpoint components, how multiple measurements were combined, or what model was used for repeated measurements.

Over-dispersion is a general statistical issue that arises when observed variability is larger than a model expects. If a model underestimates variability, standard errors can be too small and confidence intervals can be too narrow. Appropriate methods depend on the outcome and analysis structure. The registry record does not report whether over-dispersion was assessed or how variability was modeled, so no claim can be made about its role in this analysis.

Design and analysis population

The registry labels the overall study randomized and parallel, while defining the primary analysis population through completion of both a reference-alone period and a combination period. That population definition identifies which subjects are eligible for the stated comparison; it does not, by itself, describe whether the analysis treated the measurements as paired, how missing observations were handled, or whether covariates were included. Those analytic details are not reported in the registry record. The listed genotype groups provide context for the clopidogrel regimens, but the record does not report subgroup estimates or the statistical approach used for genotype-related comparisons.

The record lists two outcome measures and no analyses. It does not report a statistical analysis plan, a model specification, hypothesis-testing procedures, or an adjustment for multiple comparisons. The absence of an analysis description limits the ability to judge how the reported confidence intervals would account for the several treatment and stimulation conditions. Since numerical results are also absent, the analysis cannot be independently checked against the outcome definition.

Planning calculations are not trial findings

General sample-size illustrations can show how a hypothetical study might be planned for a stated effect size and assumptions. The registry’s planning framework describes a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of an observed effect. Such calculations are planning illustrations, not evidence about the trial’s actual power and not a substitute for its endpoint estimates. The record does not report the trial’s own sample-size justification, and no numerical planning results are reported in the registry record. A planning calculation should therefore be interpreted separately from the observed analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry describes several potential sources of multiplicity: the primary endpoint uses ADP and AA stimulation; the reference medication may be acetylsalicylic acid or clopidogrel; the group descriptions include CYP2C19 genotype categories; and skin bleeding time is listed as a secondary outcome. The record lists two outcome measures and no analyses. It does not report which comparisons were designated for formal testing, whether any outcomes or subgroups were prioritized, or whether statistical adjustment for multiple comparisons was planned or applied. Without that information, the registry results cannot establish how the risk of false-positive findings across multiple comparisons was addressed.

The primary-outcome population is restricted to subjects who completed both the reference-alone and combination periods. That definition is clear about completion, but the number of subjects meeting it is not reported. The registry record does not report how missing measurements, incomplete periods, withdrawals, or other incomplete outcome data were handled. It also does not report whether all randomized subjects were included in any analysis or whether additional analysis populations were used.

The record does not report a statistical analysis plan, details of interim analyses, a trial-specific sample-size justification, or the methods used to select among possible models. It identifies the primary endpoint and its timeframe but does not provide numerical estimates or confidence intervals. These gaps limit assessment of analysis choices, missing-data assumptions, and the degree to which the reported outcome definitions map to the analyses. The posted record therefore supports a description of the intended endpoint and population, but not a full audit of the statistical analysis.

11. 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 non-serious adverse event terms

The registry lists serious adverse events, other adverse events, and deaths separately by treatment group. Serious adverse events are listed as 0 for Cilostazol among 77 at risk, 0 for Acetylsalicylic Acid among 20 at risk, 0 for Clopidogrel among 55 at risk, 0 for Acetylsalicylic Acid - Cilostazol among 20 at risk, and 0 for Clopidogrel - Cilostazol among 55 at risk. Deaths are listed as 0 in each of these groups.

Other adverse events are listed as affecting 62 of 77 in the Cilostazol group, 3 of 20 in the Acetylsalicylic Acid group, 3 of 55 in the Clopidogrel group, 10 of 20 in the Acetylsalicylic Acid - Cilostazol group, and 41 of 55 in the Clopidogrel - Cilostazol group. These are group-level counts, not a statistical comparison. The registry does not report whether a subject could be counted in more than one treatment group, how adverse events were defined or collected, or the event terms underlying the counts. The counts should not be interpreted as estimates of comparative risk without those details and an appropriate analysis.

Zero serious adverse events in the listings means none were recorded in those group entries; it does not establish that an event is impossible or that risks are identical. These safety data are separate from the platelet-function endpoint and do not establish clinical effects.

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

The registry record establishes that this completed Phase 1 study was designed to examine platelet-function responses to cilostazol alone and in combination with acetylsalicylic acid or clopidogrel in healthy volunteers. It also specifies an ex-vivo measurement method, the combination-to-reference geometric mean ratio, a 95% confidence interval format, and an analysis population based on completion of both relevant treatment periods. These details clarify the intended scientific question.

However, numerical results for the primary endpoint are not reported in the registry record. The geometric mean ratios and their confidence intervals are therefore unavailable for interpretation. The record does not allow readers to determine the direction or magnitude of the platelet-function contrasts, how precisely they were estimated, or whether results differed between ADP and AA stimulation, reference medications, or genotype groups. Skin bleeding time is listed as a secondary outcome, but numerical results for it are also not reported.

The endpoint is a laboratory measure of platelet aggregation in platelet-rich plasma after stimulation. It does not, by itself, describe a clinical outcome. The registry does not report clinical-event results that would connect the laboratory measurements to patient outcomes. In addition, the participants were healthy volunteers, so the record does not establish how findings would apply to people with a medical condition or to settings beyond the study population.

The adverse-event listings provide counts by treatment group, including zero serious adverse events and zero deaths. They do not replace the missing primary-outcome estimates or establish comparative safety. Overall, the record communicates what the investigators intended to measure and how the endpoint was defined, but it does not provide the results needed to quantify the observed treatment contrasts or their uncertainty.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of why an endpoint definition is not the same as an endpoint result. The registry identifies a laboratory outcome, describes how aggregation was stimulated and measured, names the comparison of interest, and defines the population eligible for the primary analysis. Those details help readers understand what a reported estimate would represent. Yet without the estimates and confidence intervals, the endpoint cannot be interpreted quantitatively.

The study also illustrates the need to distinguish the overall design label from the structure of a particular analysis. The record labels the trial randomized and parallel, while the primary analysis population is defined by completion of both a reference-alone period and a combination period. That distinction makes the statistical analysis description important: readers need to know how the two observations were modeled and how incomplete data were handled. The registry does not report those details.

The treatment and measurement structure introduces multiple potential contrasts: two reference medications, two stimulation conditions, and genotype-defined groups for clopidogrel. The registry does not report an analysis plan or multiplicity strategy. Without that context, it is not possible to determine how results across those contrasts would be interpreted together.

Finally, the record separates laboratory outcomes from safety listings and clinical outcomes. The adverse-event counts can describe what was recorded by group, but they do not explain the primary platelet-function estimate. A useful statistical reading keeps each evidence type in its proper role and recognizes that absent estimates leave important questions unanswered.

14. 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 limitation for interpreting this record is that numerical primary-outcome estimates and their 95% confidence intervals are not reported in the registry record. Although the endpoint definition specifies geometric mean ratios for combinations compared with reference medications alone, the posted results do not show the ratios or interval endpoints. The registry also does not report numerical skin bleeding-time results.

The primary analysis population requires completion of both specified treatment periods, but the number of subjects in that population is not reported. The record does not describe missing-data handling, incomplete treatment periods, or the treatment of subjects who did not meet the analysis-population definition. Enrollment of 77 therefore does not identify the number contributing to the primary endpoint.

The registry labels the study randomized and parallel, and also describes successive treatment periods within its groups. It does not explain the relationship between those descriptions or give details of the analysis model. The statistical handling of within-subject measurements, genotype groups, stimulation conditions, and treatment comparisons is not reported. Nor does the record report a multiplicity strategy or a statistical analysis plan.

The acetylsalicylic acid group description is truncated during its combination-period text. The record does not report the trial’s own sample-size justification, interim analyses, or the rationale for the genotype groups. The healthy-volunteer population and ex-vivo endpoint also define a limited scope: the record does not provide clinical outcome results or show how the laboratory measure relates to outcomes outside this study. These limitations constrain both quantitative interpretation and the assessment of how broadly the findings might apply.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacodynamic Study of Cilostazol in Healthy Volunteers — NCT02554721.
• Registry record last updated 2021-10-13; status last verified 2021-09.
• Results first posted 2021-10-13.
• 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.

18. Record Summary

NCT02554721 is a completed Phase 1 randomized, unmasked, parallel study in healthy volunteers, with enrollment of 77. It examined cilostazol alone and in combination with acetylsalicylic acid or clopidogrel. The primary endpoint was ex-vivo inhibition of platelet aggregation, measured using light transmission aggregometry after ADP or AA stimulation and expressed as geometric mean ratios for combination treatment versus the corresponding reference medication alone. The endpoint timeframe was baseline and Visit 5 (Day 22-29).

The primary analysis population was defined as subjects who completed both the reference-alone and combination periods. Skin bleeding time was listed as a secondary outcome. The registry reports adverse-event counts by treatment group, including 0 serious adverse events and 0 deaths in each group. Numerical primary-outcome estimates, confidence intervals, skin bleeding-time results, analysis methods, and missing-data procedures are not reported in the registry record.