The Spot Sign for Predicting and Treating ICH Growth Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Spot Sign for Predicting and Treating ICH Growth Study (NCT00810888), a randomized phase 2 study. The primary outcome is Number of Study Subjects With Life-threatening Thromboembolic Complications.

2. Clinical Question

3. Trial Design

The registry describes a phase 2, randomized, quadruple-masked, parallel-group study sponsored by the University of Cincinnati. The condition listed is intracerebral hemorrhage. Enrollment is recorded as 92, the study status is completed, the start is listed as 2010-11, and primary completion as 2016-04. These record entries describe the study as registered; they do not establish that every enrolled participant contributed to every endpoint.

CTA spot-sign status determined the pathway described in the arm records. Spot-sign-positive participants eligible for randomization were assigned to recombinant activated factor VII or placebo. The randomized arm records list 10 participants in the study-drug group and 9 in the placebo group. Spot-sign-negative participants were followed prospectively in an observation-only arm, which lists 73 participants. Because that group was not randomized to treatment, comparisons involving it cannot be interpreted in the same way as the randomized comparison.

The brief summary describes two related aims: assessing whether CTA can predict significant hemorrhage growth, and comparing rFVIIa with placebo for hemorrhage growth among people considered at high risk. The posted primary outcome analyzed in the registry record is instead a count of participants with life-threatening thromboembolic complications through day 4 after study drug administration. The record also lists secondary outcomes relating to other potential study-drug complications, modified Rankin Scale outcome, agreement on spot-sign identification, and change in hemorrhage volume.

The registry reports quadruple masking but does not identify which groups of people were masked in the record details available for this analysis. Further operational details, including the method of random sequence generation and allocation concealment, 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The analysis population consists of 19 subjects diagnosed as "Spot Positive" on CT who were eligible for randomization within the clinical trial portion of the protocol, as well as 73 subjects diagnosed as "Spot Negative" on CT who were followed prospectively with no study intervention. Statistical comparison involves only Group1 and Group 2.

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: The baseline population consists of 19 subjects diagnosed as "Spot Positive" on CT and were eligible for randomization within the clinical trial portion of the protocol. In addition 73 subjects diagnosed as "Spot Negative" on CT were followed prospectively with no study intervention. All 92 subjects were followed to 90 days post stroke.

6. Primary Endpoint

The registry lists the primary outcome as Number of Study Subjects With Life-threatening Thromboembolic Complications, measured over through day 4 after completion of study drug administration.

The primary endpoint counts participants who experienced a life-threatening thromboembolic complication through day 4 after completion of study drug administration. The registry definition includes acute myocardial ischemia, acute cerebral ischemia, or acute pulmonary embolism. It is a binary participant-level outcome for analysis: each participant either meets the stated event definition during the specified period or does not.

Counting participants with an event gives a direct summary of how many people in each arm experienced a complication meeting the definition. It is distinct from counting the total number of events, since the endpoint is explicitly framed as the number of participants. The registry lists 1 participant with an event in the randomized study-drug group, 0 in the randomized placebo group, and 0 in the observation-only group.

Safety outcomes of this kind are relevant to interpreting a drug comparison because they describe events of concern during the stated follow-up window. The endpoint is narrowly defined: it does not encompass every adverse event, and the registry lists other potential study-drug-related complications separately among the secondary outcomes. The registry record does not report a confidence interval for the primary comparison or provide further detail on how events were adjudicated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General explanation: A binary endpoint classifies each participant according to whether an event occurred. For the primary endpoint, the registry counts participants who had a qualifying life-threatening thromboembolic complication during the specified period. The arm-level values are participant counts, not event rates or time-to-event estimates. The event definition includes acute myocardial ischemia, acute cerebral ischemia, and acute pulmonary embolism.

Why use Fisher Exact?

The sponsor-reported comparison uses Fisher Exact for the randomized study-drug and placebo groups. General explanation: this test evaluates how compatible the observed distribution of a binary outcome across groups is with a null hypothesis of no association between group and outcome, under the test’s assumptions. It is commonly applicable to categorical data when counts are small or sparse. Here, the primary counts include a single event in one randomized group and no events in the other, making the sparse nature of the data important to interpretation. The test does not itself produce a clinically interpretable difference or a measure of its precision.

The posted p-value is 1.00. General explanation: a p-value summarizes how unusual data at least as discordant with the null hypothesis would be under that null model and the selected testing procedure. It is not the probability that the null hypothesis is true, and it is not evidence that the groups are equivalent. Its interpretation depends on the analysis and does not replace an effect estimate with an interval.

What does a confidence interval add?

General explanation: a confidence interval expresses the uncertainty around an estimated effect, using a procedure with stated coverage properties over repeated applications. For a binary comparison, an interval can help show which effect values are more or less compatible with the data. No confidence interval or numerical effect estimate for the primary randomized comparison is reported in the registry record. Without those quantities, the magnitude and precision of the treatment contrast cannot be read from the reported p-value alone.

General explanation: sparse binary outcomes can make estimates unstable. When event counts are very low, small changes in the observed data may have substantial influence on an estimated effect, and methods that rely on large-sample approximations can be less dependable. Fisher Exact avoids relying on the usual large-sample approximation for its test, but it cannot create information that the observed event counts do not contain. It also does not resolve limitations in endpoint ascertainment, missing data, or the scope of the study population.

Which groups form the comparison?

The reported Fisher Exact analysis is explicitly between Group 1, randomized to study drug, and Group 2, randomized to placebo. This is the appropriate distinction to maintain when describing the randomized treatment comparison. Group 3 is an observation-only arm for CTA spot-sign-negative participants. It did not receive a randomized assignment to rFVIIa or placebo, so including it as if it were a randomized treatment arm would change the question and introduce a non-randomized contrast. The registry describes 19 spot-positive participants eligible for randomization and 73 spot-negative participants followed prospectively; the randomized arm records list 10 in the study-drug group and 9 in the placebo group.

The record labels the primary outcome as a count of participants and gives the timeframe as through day 4 after completion of study drug administration. It does not describe a time-to-event analysis for this outcome. General explanation: a count endpoint and a time-to-event endpoint answer different questions. A count records whether participants experienced an event within the defined period, while a time-to-event method uses event timing and may account for differing follow-up. No such timing analysis is reported for this primary outcome.

What can sample-size illustrations say?

The registry record does not report the trial’s sample-size justification or planning calculation. Any planning illustration based on an observed effect is not evidence of the trial’s observed power. General explanation: post hoc calculations that feed an observed effect into a power formula are driven by the estimated effect itself and do not show the probability that the completed study detected a true effect. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Such illustrations are planning scenarios, not observed trial outcomes or substitutes for a confidence interval.

General explanation: over-dispersion matters when count data vary more than a model’s assumed distribution allows, potentially making standard errors too small and intervals too narrow. The primary endpoint is listed as binary and as a participant count, with no dispersion measure reported. The registry record does not describe an over-dispersion model for this endpoint; applying one cannot be justified from the listed primary analysis.

Finally, methods reporting is incomplete for a full statistical audit. The record names Fisher Exact and gives the p-value, but the analysis description does not state further details such as a prespecified testing hierarchy, handling of missing endpoint observations, or adjustment for multiple outcomes. Those details are not reported in the registry record and should not be inferred from the test name.

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("Group 1 - Randomized to Study Drug", "Group 2 - Randomized to Placebo", "Group 3 - Observation Only Arm")
n      <- c(10, 9, 73)
events <- c(1, 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  Group 1 - Randomized to Study Drug  10  1  10.0  0.3  44.5  1.8  40.4  2.3  41.3
ARM  Group 2 - Randomized to Placebo  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Group 3 - Observation Only Arm  73  0  0.0  0.0  4.9  0.0  5.0  0.0  4.9

11. Analyses Reported by the Sponsor

The registry’s sponsor-reported primary analysis compares the randomized study-drug group with the randomized placebo group using Fisher Exact. It reports p = 1.00 for the superiority analysis. The posted arm counts are 1 participant with the event in the study-drug group and 0 in the placebo group. No effect estimate or confidence interval is reported for this comparison.

The record does not flag a discrepancy between the sponsor-reported result and a recalculated result. However, it also indicates that values are missing or not estimable for a two-arm comparison of this binary endpoint. Accordingly, there is no separate recalculated effect estimate to set beside the sponsor’s test result. The sponsor’s reported analysis remains the relevant posted inferential result; it should be described as a test of the randomized comparison, not as evidence that the treatments are equivalent.

General explanation: a test result and an effect estimate answer related but different questions. The p-value describes compatibility with a null hypothesis under the selected method, while an effect estimate and confidence interval describe the contrast and its uncertainty. Since the latter are not reported in the registry record, the sponsor analysis cannot be expanded into a quantitative estimate of treatment benefit or harm from the available primary outcome fields.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists 8 outcome measures and 8 analyses, and reports 4 secondary outcomes in the registry record for this analysis. Those secondary outcomes address other potentially study-drug-related complications, 90-day modified Rankin Scale outcome among spot-positive participants, agreement between clinical-site and study radiologists on spot-sign identification, and percent change in total hemorrhage volume. The primary endpoint is the count of participants with life-threatening thromboembolic complications through day 4 after study drug administration.

Multiplicity arises when several hypotheses or outcomes are assessed: the chance of at least one apparently unusual result can increase if many tests are interpreted together without an appropriate strategy. General explanation: a prespecified hierarchy or adjustment method can help define how results should be interpreted across multiple tests. The registry record does not report a multiplicity strategy, an ordered testing plan, or whether the primary result was intended to control interpretation of secondary outcomes. No adjustment should therefore be assumed.

The analysis population description identifies 19 spot-positive participants eligible for randomization and 73 spot-negative participants followed prospectively without study intervention. The posted primary arm counts are 10 for the study-drug group, 9 for placebo, and 73 for observation. The registry record does not explain whether these figures reflect all enrolled participants, endpoint availability, or another analysis-population rule. It does not report a clearly named intention-to-treat or per-protocol population for this result.

Missing endpoint data, withdrawals, exclusions, and the handling of participants with incomplete follow-up are not reported in the registry record. The record also does not describe imputation or sensitivity analyses for missing primary outcomes. Those omissions matter because the interpretation of a participant count depends on knowing who was assessed and how unavailable outcome information was handled. The available result should therefore be read as the posted arm counts and test, without assuming complete ascertainment or a particular missing-data method.

The record does not report interim analyses, stopping rules, or details of the statistical analysis plan beyond the named test and result. These items should be treated as unreported, rather than reconstructed from the fact that the study is completed.

13. 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: seizure (22.2%), respiratory distress (20.0%), cerebral edema (11.1%), weakness left leg (11.1%), slurred speech (11.1%).

For the primary life-threatening thromboembolic endpoint, the registry records 1 participant with an event in the randomized study-drug group, 0 in the randomized placebo group, and 0 in the observation-only group. These are participant counts through day 4 after completion of study drug administration. The primary analysis compares the two randomized groups, not the observation arm.

Separate adverse-event fields report serious adverse events affecting 4 participants in the study-drug group, 4 in the placebo group, and 16 in the observation group. Other adverse events are reported for 9, 8, and 65 participants in those respective groups. Deaths are recorded as 2, 0, and 4, respectively. These fields are separate from the primary endpoint and should not be treated as interchangeable counts. The registry does not report in the registry record whether participants could contribute to more than one adverse-event category or how all events were attributed.

The listed serious-event terms include seizure (22.2%), respiratory distress (20.0%), cerebral edema (11.1%), weakness left leg (11.1%), slurred speech (11.1%), and gram negative bacteremia (10.0%). The denominators underlying these term percentages are not reported in the registry record, so they should not be converted into participant counts or compared as if their denominators were known.

These figures are descriptive safety information. Differences in raw counts across the randomized and observation groups do not by themselves establish a treatment effect, particularly because the observation group was not randomized and the groups have different study pathways. The registry record does not provide uncertainty intervals for these adverse-event comparisons.

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

The primary result establishes what was recorded for the specified endpoint and period: 1 participant in the randomized study-drug group had a qualifying life-threatening thromboembolic complication, while no such participants were recorded in the placebo or observation-only groups. The sponsor-reported Fisher Exact result for the randomized comparison is p = 1.00. This describes the posted analysis; it does not establish that rFVIIa and placebo have the same effect.

The result also does not establish a reliable difference in risk. Sparse event counts leave considerable uncertainty about the range of effects that might be compatible with the data, and the registry does not report an effect estimate or confidence interval for the primary comparison. A zero count is not proof that the event is impossible, while an event in one arm does not by itself show that treatment caused it. The p-value cannot substitute for an interval estimate or a clinical assessment of the possible consequences of the event.

The observation group must be interpreted separately. Those participants were spot-sign negative and followed without study intervention; they were not randomized to either treatment. Their primary event count is descriptive and cannot be used as a randomized comparison with either treatment arm. Similarly, the primary result is not a direct answer to the study’s broader stated aim about whether CTA predicts hemorrhage growth.

The record lists other secondary outcomes, including hemorrhage-volume change and functional outcome, but their results are not reported in the registry record for this analysis. The primary thromboembolic count therefore cannot be used to infer results for those outcomes. Nor does this result establish a conclusion about every potential adverse event, since the primary definition covers only the listed life-threatening thromboembolic complications within its stated timeframe.

In short, the registry reports a sparse primary outcome and a sponsor-reported test for the randomized contrast. It does not provide the precision measures needed to characterize the size of that contrast, and it does not support claims of equivalence, definitive benefit, or definitive harm. The appropriate reading is limited to the stated endpoint, analysis groups, and recorded counts.

15. Why This Trial Matters Statistically

This study illustrates why the distinction between prediction, treatment comparison, and observation matters. CTA spot-sign status divided participants into different study pathways: spot-sign-positive participants eligible for randomization entered the rFVIIa-versus-placebo comparison, while spot-sign-negative participants were followed in an observation-only group. These pathways address related clinical questions but do not create one interchangeable set of treatment arms.

The primary endpoint also shows how a safety question can differ from a study’s broader aims. The brief summary describes prediction of hemorrhage growth and the treatment comparison for high-risk participants. The primary posted analysis instead counts life-threatening thromboembolic complications during the specified post-administration period. Statistical interpretation must track the endpoint actually analyzed rather than letting the broader study rationale stand in for the reported result.

The result is a useful example of sparse binary data. A named exact test can be appropriate for a small categorical dataset, but the test cannot make an imprecise result precise. Reporting an effect estimate and confidence interval alongside counts would help readers judge the range of effects compatible with the data; those measures are not reported for this primary comparison. A p-value alone is particularly limited when the event count is low.

The record also highlights the importance of transparent analysis-population and missing-data reporting. The record identifies the groups and their counts, but does not explain how incomplete follow-up or missing endpoint information was handled. It does not report a multiplicity strategy for the several outcomes listed. Those omissions constrain what can be inferred even when the endpoint and test are named.

For clinical researchers and biostatisticians, the key lesson is not a treatment conclusion. It is that design, endpoint definition, group formation, event sparsity, and reporting precision all shape the meaning of a trial result. Keeping the randomized comparison distinct from the observation cohort and separating the primary safety outcome from the broader aims prevents overstatement.

16. Limitations

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

The primary comparison is based on sparse event counts: the record lists 1 event in the randomized study-drug group and 0 in the randomized placebo group. Such data limit how precisely a treatment contrast can be estimated. The registry record does not report a confidence interval or numerical effect estimate, leaving the magnitude and uncertainty of the contrast unquantified in the posted primary result.

The observation-only group is not a randomized comparator. It comprises spot-sign-negative participants followed without study intervention, whereas the randomized comparison concerns spot-sign-positive participants eligible for randomization. Any direct comparison between that group and a randomized arm would mix treatment assignment with differences in CTA classification and study pathway.

Analysis-population details are limited. Although the record describes the eligible spot-positive and observed spot-negative populations and lists arm counts, it does not explain the relationship between enrollment, endpoint availability, and the analyzed participants. Missing data, withdrawal handling, and sensitivity analyses are not reported in the registry record. The specific roles covered by quadruple masking are also not reported in the registry record.

The registry reports a Fisher Exact test and p = 1.00, but not a multiplicity strategy, interim-analysis details, or the statistical plan beyond the named analysis. The record lists multiple outcomes, so the absence of a reported testing hierarchy limits interpretation across outcomes. Results for the listed secondary outcomes are not included in the registry record for this analysis, which prevents assessment of the study’s other stated questions.

Finally, the primary endpoint covers a defined set of life-threatening thromboembolic complications through day 4 after study drug administration. It should not be treated as a complete account of all safety outcomes or as a measure of longer-term risk. These limitations do not invalidate the posted counts; they define the scope of what those counts and the reported test can support.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: The Spot Sign for Predicting and Treating ICH Growth Study — NCT00810888.
• Registry record last updated 2018-03-16; status last verified 2018-02.
• Results first posted 2018-01-08.
• 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.

20. Record Summary

The registry describes a completed, phase 2, randomized, quadruple-masked, parallel-group study sponsored by the University of Cincinnati, with enrollment recorded as 92. Spot-sign-positive participants eligible for randomization were assigned to recombinant activated factor VII or placebo; spot-sign-negative participants were followed in an observation-only group.

The primary endpoint counts participants with a life-threatening thromboembolic complication through day 4 after study drug administration. The posted counts are 1 in the study-drug group, 0 in placebo, and 0 in observation. The sponsor-reported Fisher Exact comparison of the randomized groups gives p = 1.00. No effect estimate or confidence interval is reported for that comparison.

The registry also lists secondary outcomes and adverse-event counts. Details of multiplicity handling, missing-data methods, and the analysis population are not reported in the registry record. The primary result should be read as a sparse endpoint count and test for the randomized comparison, not as a definitive conclusion about treatment equivalence or the broader study aims.