Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II (NCT00130039), a randomized phase 4 study. The primary outcome is Number of Participants With Progression of Symptomatic Intracranial Stenosis.

2. Clinical Question

The trial addresses whether the number of participants with imaging-defined progression differed between the two assigned drug groups. Progression was defined by a worsening of at least one stenosis grade on the symptomatic artery between baseline and final magnetic resonance angiography. The registry describes five grades, from normal through occlusion, and states that blind reviewers classified the images.

This is an imaging outcome rather than a direct measure of symptoms or disability. The registry also lists outcomes involving new magnetic resonance imaging lesions, stroke events, overall cardiovascular events, ipsilateral ischemic stroke, and fatal or major bleeding complications. Those outcomes provide additional clinical context, but they are distinct from the primary imaging question.

3. Trial Design

NCT00130039, titled “Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II,” is recorded as a phase 4 randomized, quadruple-masked, parallel-group trial. Asan Medical Center is listed as the sponsor. The registry status is completed; the recorded start is 2005-08 and the primary completion is 2009-01.

The registry reports enrollment of 457. Its brief summary says the study would recruit 480 acute stroke patients with symptomatic intracranial stenosis involving the M1 segment of the middle cerebral artery or the basilar artery. The record does not explain the difference between the enrollment figure and the planned recruitment figure in that summary.

Participants were randomly assigned to cilostazol or clopidogrel. The cilostazol arm is described as cilostazol 100mg twice daily plus a clopidogrel placebo; the clopidogrel arm is described as clopidogrel 75mg once daily plus a cilostazol placebo. The summary states that every participant would also take aspirin 100mg a day. Quadruple masking is recorded, but the registry record does not identify which specific roles were masked.

The primary outcome was assessed 7 months after treatment. The secondary outcome timeframes are described as up to 7 months after randomization, so the registry uses different wording for the primary and secondary timepoints. The record does not give further detail on follow-up schedules or on how the analysis population was defined.

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: The excluded patients did not satisfy the definition of the symptomatic stenosis of our study protocol.

Overall Study

Reasons for not completing this period:

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 Participants With Progression of Symptomatic Intracranial Stenosis, measured over 7 months after treatment.

The primary endpoint is the number of participants with progression of symptomatic intracranial stenosis. The registry defines progression as worsening by at least one grade on the symptomatic artery at final magnetic resonance angiography compared with baseline. Reviewers classified stenosis on the middle cerebral arteries and basilar artery using five grades: normal, mild, moderate, severe, and occlusion. The registry says that the reviewers were blind to treatment assignment.

This endpoint turns a change in an imaging classification into a participant-level event: a participant either meets the stated progression definition or does not. It can therefore be compared between the randomized groups as an event count and as a difference in event risk. The outcome is specific to the artery identified as symptomatic, rather than a measure of any imaging change in any artery.

Imaging progression is used as a measurable indicator of change in stenosis over follow-up. It is not itself a count of strokes, a measure of disability, or a direct account of how participants felt. The registry lists stroke and other clinical events separately as secondary outcomes. The primary assessment is specified at 7 months after treatment, and the registry record does not provide further information about how missing or unreadable scans were handled.

7. Results Posted in the Registry

• Clopidogrel: 15.5% (32/207) versus 9.9% (20/202) on control; risk difference 5.6 percentage points (95% CI -0.9 to 12.0), risk ratio 1.56 (0.92–2.64); unadjusted two-proportion z-test p = 0.092.

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.

Number of Participants With Stroke Events

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Clopidogrel: 3.1% (7/225) versus 4.7% (11/232) on control; risk difference -1.6 percentage points (95% CI -5.2 to 1.9), risk ratio 0.66 (0.26–1.66); unadjusted two-proportion z-test p = 0.370.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Clopidogrel and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With Overall Cardiovascular Events

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Clopidogrel: 4.4% (10/225) versus 6.5% (15/232) on control; risk difference -2.0 percentage points (95% CI -6.2 to 2.1), risk ratio 0.69 (0.32–1.50); unadjusted two-proportion z-test p = 0.342.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Clopidogrel and the control. The interval gives the range of effects that remain compatible with the data.

Number of Patients With Ipsilateral Ischemic Stroke Rate

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Clopidogrel: 2.2% (5/225) versus 3.9% (9/232) on control; risk difference -1.7 percentage points (95% CI -4.8 to 1.5), risk ratio 0.57 (0.19–1.68); unadjusted two-proportion z-test p = 0.304.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Clopidogrel and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists five secondary outcomes, but numeric results are posted for three: stroke events, overall cardiovascular events, and ipsilateral ischemic stroke. For each of these, the posted unadjusted comparison is uncertain, and its confidence interval includes no difference. The observed group directions are not uniform across outcomes, so the secondary results do not form a consistent pattern that independently clarifies the primary imaging result.

These clinical-event outcomes address questions distinct from progression on magnetic resonance angiography. They can add context about events that matter clinically, but they do not directly confirm or refute the imaging endpoint. The registry does not report numerical results for new MRI lesions or fatal or major bleeding complications; those outcomes are not available for comparison in the posted results.

Unadjusted secondary findings carry less weight because several outcomes are examined. When multiple comparisons are made, the chance of at least one apparently notable result due to random variation can increase. A multiplicity plan can specify how to account for that issue, but one is not reported in the registry record. The record also gives no reported formal analyses for these secondary comparisons.

The secondary outcomes should therefore be read as additional descriptive evidence rather than as a set of separate confirmatory tests. Their uncertain comparisons and incomplete reporting constrain how much they can contribute to an overall interpretation. They do not change the central statistical reading of the primary endpoint: the observed progression counts differed, but the primary interval included no difference.

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

• Number of Participants With New MRI (Magnetic Resonance Image) Lesions on Follow-up MRI
• Number of Participants With Stroke Events
• Number of Participants With Overall Cardiovascular Events
• Number of Patients With Ipsilateral Ischemic Stroke Rate
• Numbers of Fatal or Major Bleeding Complications

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: progression is either recorded or not recorded under the registry definition. For such an outcome, a group risk is the proportion of participants in that group who experienced the event. A risk difference subtracts one group’s risk from the other’s. Here, the posted comparison is clopidogrel relative to cilostazol, so a positive estimate corresponds to a higher observed risk in the clopidogrel group. The posted result is unadjusted; the registry record does not report an adjusted model for this comparison.

What does the confidence interval describe?

A confidence interval describes the statistical uncertainty around an estimated effect under the method used to construct it. It gives a range of values reasonably compatible with the observed data and the model assumptions. It does not mean that there is a specified probability that the true effect lies in this particular interval. For the primary risk difference, the interval includes zero, the value corresponding to no group difference. That is consistent with the unadjusted p-value of 0.092: the result does not provide strong evidence against a no-difference comparison under a conventional significance threshold.

What does the p-value tell us?

A p-value is calculated under a null hypothesis and statistical assumptions. It measures how incompatible the observed data, or data more extreme, are with that null hypothesis. It is not the probability that the treatment effect is zero, and it does not measure the size or clinical importance of an effect. A p-value also does not resolve concerns about missing outcomes, population definitions, or multiple comparisons. The registry posts unadjusted p-values for the primary and available secondary comparisons and does not report an analysis plan explaining how those comparisons were selected or interpreted.

Why might other effect measures appear?

For a binary event, a risk ratio compares the event risks in two groups by division, while an odds ratio compares the odds of the event. These measures express relative rather than absolute differences and answer different descriptive questions from the risk difference. The posted comparisons include alternative relative measures, but the registry’s primary outcome is reported as a participant count and the main comparison is a risk difference. Any relative measure still depends on the observed events and should be read with its uncertainty interval, not as a measure of certainty by itself.

Why does the endpoint definition matter?

The progression result depends on the registry’s threshold: a worsening of at least one stenosis grade on the symptomatic artery between baseline and final imaging. A different threshold or a different method of classifying scans could define a different event. The registry says blind reviewers classified severity, which helps separate image assessment from knowledge of assigned treatment. It does not report further details about reviewer agreement, adjudication, or how images that could not be classified were handled.

What information is missing about the analysis?

The registry reports no formal analysis descriptions for the posted outcomes. It does not report a statistical analysis plan, a model specification, adjustment factors, interim analyses, the intended handling of missing data, or analysis-population definitions. Those omissions matter because they limit assessment of whether the posted comparisons followed a prespecified plan and how sensitive they might be to analytic choices. The registry record also does not give the trial’s original sample-size assumptions or justification. The planning illustrations are separate calculations based on observed effects, not a record of the trial’s design rationale.

For the primary result, the available description supports a straightforward reading of the two event counts and the unadjusted risk-difference comparison. It does not support claims about covariate-adjusted effects, treatment adherence, subgroup effects, or time-to-event patterns. The primary endpoint is a fixed-time imaging event, and the registry reports neither event times nor a time-to-event analysis. Keeping the interpretation aligned with the design and the information actually recorded avoids attributing methods or certainty that the registry does not document.

11. Confidence Intervals and Precision

Precision concerns how tightly the data estimate a group difference. The primary risk-difference estimate is positive for clopidogrel relative to cilostazol, but its confidence interval crosses zero. Thus, the data are compatible with no difference as well as with differences in either direction. The interval is wide enough that the point estimate should not be treated as a precise measure of the size of any group effect.

The unadjusted p-value for the primary comparison is 0.092. A p-value and confidence interval describe related aspects of the same comparison, but the interval is particularly useful for seeing the range of effect sizes consistent with the data. The fact that the interval includes zero does not establish equivalence; an equivalence conclusion would require a prespecified margin and an analysis designed for that question. Such a margin is not reported in the registry record.

The event counts are modest relative to their group denominators, which limits the information available about differences in event risk. This is a general statistical reason that binary outcomes with relatively few events may yield broad intervals. The registry does not report a trial-specific precision target or the original assumptions used to plan enrollment, so the observed uncertainty cannot be compared with a documented design target.

The secondary comparisons are also uncertain, and their intervals include no difference. Their interpretation is further limited by the number of outcomes considered and the absence of a reported multiplicity plan. The precision of the estimates should therefore be distinguished from whether a result crosses a conventional significance threshold: the interval conveys uncertainty about plausible effect sizes, while the threshold does not make that uncertainty disappear.

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 illustrations based on the observed effect, not the trial’s original design assumptions. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The registry record does not report the trial’s own sample-size justification or original planning assumptions.

The figures are participants per arm for 80% power and participants per arm for 90% power. In general, power is the chance that a study using the stated assumptions would reject the null hypothesis if the specified effect were the true effect. The 90% power column targets a greater chance of detecting that effect than the 80% power column, and therefore calls for more participants per arm under the same assumptions.

Rows that plan for 100% of the observed effect use the full observed effect as the target for a future study. Rows that plan for 75% or 50% of the observed effect use smaller targets. Smaller effects are harder to distinguish from random variation, so the planning illustrations require more participants per arm as the target effect becomes smaller. The participant counts depend on the assumed effect and calculation method; they are not predictions of the size of a future trial.

These figures are not observed power. Observed power would use the effect estimated from the completed study and does not provide a useful substitute for reading the confidence interval and the uncertainty in the effect estimate. The planning illustrations also do not establish whether the completed trial was adequately sized under its original protocol, because that protocol-specific rationale is not reported in the registry record.

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 = 0.099; treatment proportion p₁ = 0.155; average p̄ = 0.127.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4706 = 0.9223.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4689 = 0.3947.
4. n = (0.9223 + 0.3947)² / (0.0556)² = 561.5, rounded up to 562 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 <- 0.099009900990099                          # control proportion
p1 <- 0.154589371980676                          # 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(130039)
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 = 562 (80% power), 752 (90% power)
 75% of observed effect: n per arm = 952 (80% power), 1,274 (90% power)
 50% of observed effect: n per arm = 2,035 (80% power), 2,724 (90% power)
power.prop.test: 561.5 
Simulated power at n = 562 per arm: 0.804 (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. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome and five secondary outcomes. It posts numerical results for the primary outcome and three secondary outcomes, but the analyses are not accompanied by a reported multiplicity strategy. When several outcomes are tested, interpreting each unadjusted p-value as if it were the sole planned test can overstate the strength of evidence across the set. The record does not say whether a hierarchy, adjustment procedure, or other control of multiple comparisons was prespecified.

Missing-data methods are also not reported in the registry record. The record does not explain whether all randomized participants had an evaluable primary scan, how unavailable or unreadable scans were treated, or whether any imputation was used. It also does not state whether the analysis followed intention-to-treat, per-protocol, or another population definition. These details matter because missing outcomes and choices about which participants enter an analysis can affect the estimated event risks.

The denominators vary across outcome records: the primary comparison uses 202 and 207, while the posted secondary and adverse-event records use 232 and 225. The registry does not explain the differing denominators or identify the underlying analysis populations. The differences should be noted rather than resolved by assumption.

The record does not report interim analyses, stopping rules, or a statistical analysis plan. Without these details, it is not possible to assess whether the posted analyses followed a prespecified sequence or how missing observations and multiple outcomes were handled. These are reporting limitations, not evidence that a particular method was or was not used.

15. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cerebral infarction (4.3%), fracture or other joint pain (3.1%), gi bleeding (2.7%), depression (2.6%), gastroenteritis (2.2%).

The serious adverse-event records list 54 affected participants in each group. The associated at-risk denominators are 232 for cilostazol and 225 for clopidogrel. These are safety-record figures and are not the same denominators used for the primary outcome. The registry also lists serious adverse-event terms with percentages, including cerebral infarction at 4.3%, fracture or other joint pain at 3.1%, and GI bleeding at 2.7%. Other listed terms are depression at 2.6%, gastroenteritis at 2.2%, and diabetes complications at 1.8%.

These figures describe events recorded in the registry; they do not establish that a treatment caused an event. The record does not provide enough detail to infer comparative risk for each listed term, and it does not report deaths in the adverse-event fields. The listed percentages should be read as reported, not as a substitute for an arm-specific analysis of each event.

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

The primary result means that progression, as defined by the registry’s imaging criteria, was recorded in 20 participants assigned to cilostazol and 32 assigned to clopidogrel. The group denominators were 202 and 207. The estimated risk difference favored fewer observed progression events with cilostazol, but the confidence interval included zero and the unadjusted p-value was 0.092. This is an uncertain comparison, not a definitive demonstration of a difference.

It also does not demonstrate that the treatments are equivalent. A result that does not rule out no difference is not the same as evidence that any difference is small enough to be unimportant. The registry record does not report an equivalence or non-inferiority margin or a design intended to establish equivalence.

The endpoint concerns imaging-defined progression on the symptomatic artery at the stated follow-up. It does not by itself show whether participants experienced symptoms, disability, or other benefits or harms. Stroke and cardiovascular events are listed separately, and their posted comparisons are also uncertain. Results for two listed secondary outcomes are not reported in the registry record.

The trial record provides limited information about analysis populations, missing scans, and multiplicity. The denominators differ across outcome records, and the reason is not reported. These limits make it important to avoid extending the primary comparison beyond the outcome and participants represented in the posted analysis.

In short, the posted data document a numerical difference in progression counts, with more events observed in the clopidogrel group, but the uncertainty around the comparison remains substantial. The record does not support a conclusive claim that one treatment is better or worse, nor does it answer all clinical questions about the two treatment strategies.

17. Why This Trial Matters Statistically

This trial illustrates why event counts, estimated effects, and uncertainty need to be read together. The primary counts differ, and the estimated risk difference points in one direction, but its confidence interval includes no difference. Reporting only the direction of the counts would make the evidence appear more decisive than the interval supports; reporting only a p-value would hide the range of effect sizes compatible with the data.

It also shows the value of a clear endpoint definition. The registry defines progression through a change in stenosis grade on the symptomatic artery and states that blind reviewers classified the images. That definition makes the imaging event more interpretable, while still distinguishing it from clinical events such as stroke. Keeping those outcomes separate avoids treating an imaging measure as if it were a direct measure of every aspect of health.

Finally, the record demonstrates how missing analysis details affect interpretation. The absence of a reported multiplicity plan, missing-data approach, and analysis-population definitions limits what can be concluded from the unadjusted comparisons. Different denominators across outcome records also warrant attention. These are important considerations when evaluating registry results, even when the outcome counts themselves are clearly stated.

18. Limitations

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

The registry record has several trial-specific reporting limitations. It gives enrollment as 457 while the brief summary describes a plan to recruit 480, without explaining the difference. The primary outcome denominators differ from those recorded for the secondary outcomes and adverse events, and the record does not explain why. It does not state how many participants had unavailable or unevaluable imaging, or how missing outcomes were handled.

The record does not report a statistical analysis plan, analysis-population definitions, adjustment factors, interim analyses, or the trial’s original sample-size rationale. It also does not report how the five secondary outcomes were prioritized or whether their comparisons were adjusted for multiplicity. Numerical results are absent for the outcomes concerning new MRI lesions and fatal or major bleeding complications.

The primary endpoint is a fixed-time imaging classification, not a time-to-event outcome or a direct measure of symptoms or disability. The registry gives the classification grades and progression threshold but does not describe reviewer agreement or adjudication beyond noting blind review. The primary timeframe is stated as 7 months after treatment, while secondary outcomes are described as up to 7 months after randomization. The registry record does not clarify that wording difference.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II — NCT00130039.
• Registry record last updated 2010-01-12; status last verified 2009-11.
• Results first posted 2010-01-01.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

NCT00130039 is a completed, randomized, quadruple-masked, parallel-group phase 4 trial sponsored by Asan Medical Center. It compared cilostazol with clopidogrel in acute stroke patients with symptomatic intracranial stenosis; the registry summary states that participants also took aspirin 100mg a day. Enrollment is recorded as 457.

The primary outcome was the number of participants with progression of symptomatic stenosis on magnetic resonance angiography at 7 months after treatment. Progression was recorded in 20 participants in the cilostazol group and 32 in the clopidogrel group. The unadjusted comparison is uncertain, with a confidence interval that includes no difference and p = 0.092. The registry does not report several analysis details needed to assess missing data, population definitions, or multiplicity.