A Study of Intra-thrombus Plasmin (Human) In Acute Peripheral Arterial Occlusion: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Intra-thrombus Plasmin (Human) In Acute Peripheral Arterial Occlusion (NCT01222117), a randomized phase 2 study. The primary outcome is The Proportion of Subjects With >50% Thrombolysis.

2. Clinical Question

This was a Phase 2 study focused on how plasmin was delivered and on its safety and tolerability. It was randomized, but the plasmin groups were open-label while the plasminogen activator and placebo groups were blinded. That distinction matters when interpreting outcomes: the endpoint was assessed by arteriography, but the record does not say whether image readers were blinded to group assignment or describe other safeguards against assessment bias.

The trial included many regimen arms, and their procedures differed in more than one respect. Some used an initial proximal pulse, some used a balloon occlusion catheter, and infusion duration and rate also varied. Therefore, the study question is broader than a simple comparison of one treatment with one control. The results describe observed endpoint proportions by group, but without reported inferential analyses they do not establish the size or precision of differences between regimens.

3. Trial Design

The registry describes a completed Phase 2, randomized, open-label, parallel-group study with enrollment of 174. Its start was recorded as 2010-12 and its primary completion as 2015-12. The sponsor was Grifols Therapeutics LLC. Although the overall study was open-label, the plasminogen activator and placebo groups were blinded; the plasmin regimens were open-label.

The study compared multiple delivery regimens of intra-thrombus plasmin in acute lower extremity native artery or bypass graft occlusion. Most plasmin arms used 150 mg, with differences in pulse administration, infusion duration and rate, and use of a balloon occlusion catheter. Group M used 250 mg with a 5-hour infusion and a balloon occlusion catheter. The plasminogen activator arm used a dose and volume according to the investigator’s clinical judgement or standard practice. Its placebo group received normal saline for injection under the corresponding administration practice.

The primary endpoint was measured at the end of treatment, with the endpoint timeframe listed as 5 hours for groups A, B, C, G, I, and M, and 2 hours for groups D, H, and J. The listed primary endpoint groups do not include the plasminogen activator or placebo groups in that timeframe description, although results are posted for both controls. The registry record does not explain that difference.

The stated overall enrollment and the group-level endpoint counts are distinct pieces of information. For the primary endpoint, the record notes that some participants were excluded from assessment for missing or unreadable end-of-treatment arteriograms, insufficient dose, or catheter-related reasons, depending on group. The full endpoint population definition is truncated in the record available for this analysis. Allocation concealment, randomization method, target enrollment per arm, and the sample-size justification are not reported in the registry record.

The design can support a descriptive look across varied delivery strategies, but the regimen arms differ on multiple features and have small posted endpoint counts in several groups. Without a stated primary pairwise contrast and reported adjusted analyses, the trial results should be read as group-specific endpoint summaries rather than definitive rankings of regimens.

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.

Only the first 6 of 11 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: In groups A-D, G and H, 8 subjects were excluded (EOT arteriogram missing or not read, did not receive \>=90% of dose). In groups I and J, 11 subjects were excluded (BOC not inserted/appropriately inflated, missing an arteriogram). In group F, 1 subject was not dosed and 4 subjects were excluded (did not receive \>=90% of dose).

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.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Proportion of Subjects With >50% Thrombolysis, measured over 5 hours (Treatment Groups A, B, C, G, I, M) or 2 hours (Treatment Groups D, H, J).

The primary endpoint is the proportion of participants with more than 50% thrombolysis at the end of treatment compared with baseline, assessed by arteriography. It is a binary endpoint: each participant either met the stated threshold or did not. The posted group values are expressed as percentages of participants.

Arteriography supplies an imaging-based assessment of the treated arterial occlusion. A threshold endpoint turns a continuous or graded clinical imaging assessment into a defined category, which can make results easier to summarize across participants. However, categorization also discards information about how far an individual result was from the threshold. Two participants on opposite sides of the cutoff may have relatively similar imaging findings, while participants in the same category may have different degrees of thrombolysis.

The registry describes assessment at the end of treatment, but treatment duration varied by regimen. Groups A, B, C, G, I, and M had a 5-hour timeframe; groups D, H, and J had a 2-hour timeframe. That means the endpoint’s timing is tied to the treatment regimen rather than being identical across every listed plasmin group. The registry record does not report longer-term follow-up for this primary endpoint.

The endpoint is a measure of the angiographic response at a specified treatment endpoint, not by itself a complete measure of patient experience, subsequent clinical course, or net benefit. Those broader outcomes cannot be inferred from the primary endpoint proportions alone. The registry record also does not report confidence intervals or a formal hypothesis test for the displayed proportions, so their precision and the statistical uncertainty around group differences are not quantified in the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a proportion measure?

For a binary endpoint, a proportion describes the share of assessed participants who meet a specified condition. Here, that condition was more than 50% thrombolysis at the end of treatment compared with baseline by arteriography. The posted percentages are descriptive summaries within each group. They do not, by themselves, show whether observed differences are compatible with random variation or whether a particular contrast was statistically supported.

Why does the denominator matter?

Each group’s percentage is based on its own endpoint count. When counts are small, the estimate can change substantially with the outcome of an individual participant. This is a general property of proportions, not evidence that any particular result is wrong. It is especially important to avoid treating a visually large difference between percentages as precise when the denominators are small. The record does not report confidence intervals for these endpoint proportions, so readers cannot use the posted results to assess their uncertainty through interval estimates.

What would a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate under a specified analysis. For a group proportion, it can indicate a range of values compatible with the observed data and the method’s assumptions. For a comparison, an interval for the difference or another contrast can show both direction and precision. No such intervals for the primary results are reported in the registry record. Without them, the percentages should be read as point summaries rather than precise estimates of the underlying group response rates.

How should between-group comparisons be understood?

A randomized design can help make treatment groups comparable at baseline on average, but randomization does not remove uncertainty in a study with limited endpoint counts. A formal comparison also needs a defined contrast, an analysis method, and an account of the endpoint population. The registry record lists no analyses for the outcome measures in this posting, and it does not report a primary pairwise contrast, test statistic, p-value, or adjusted effect estimate. Therefore, no claim of statistical significance can be drawn from the observed percentages alone.

The regimen arms also differ in several delivery details. A comparison of two arms would reflect the combined differences between their assigned procedures, not necessarily the isolated effect of pulse administration, infusion rate, duration, or catheter use. To estimate a single feature’s effect, a design or analysis would need to distinguish that feature from the others; the registry record does not report such an analysis.

What is the role of randomization and masking?

Random allocation is intended to reduce systematic differences between groups at the time of assignment. The record identifies the study as randomized and parallel-group, but does not report the sequence-generation or allocation-concealment procedures. The trial was open-label for plasmin treatment and blinded for the plasminogen activator and placebo groups. The record does not state whether arteriogram readers were blinded or how outcome assessment was standardized. These details matter because knowledge of assignment can affect care and, in some settings, assessment or reporting.

Why do missing outcomes matter?

The registry notes that some participants were excluded from the primary endpoint assessment because the end-of-treatment arteriogram was missing or not read, the participant did not receive at least 90% of the dose, or a balloon occlusion catheter was not inserted or appropriately inflated. These reasons vary by group. In general, analyses limited to participants with evaluable outcomes can be biased if the reasons for missingness or exclusion relate to prognosis or treatment response. The record does not provide a complete accounting of missing outcomes or a sensitivity analysis that would show how alternative assumptions affect the results.

What do planning illustrations mean?

In general, sample-size planning estimates the number of participants needed to detect a specified effect under assumptions about the statistical test, allocation, and variability. A planning illustration based on an observed effect is not observed power and is not evidence that the trial was adequately powered for its original objectives. The stated planning assumptions for this study use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect set as a fraction of the observed effect. These are illustrative assumptions; the sample-size justification used to design the trial is not reported in the registry record. The record does not report a protocol-based sample-size calculation or a prespecified effect size.

What about multiplicity?

When many groups or outcomes are examined, the chance of finding an apparently unusual result by chance can increase. Statistical methods may address this with prespecified comparisons or adjustment procedures. The registry record does not report a multiplicity plan, and it lists multiple delivery regimens without specifying which pairwise comparisons were confirmatory. Consequently, the observed ordering of group percentages should be treated as descriptive rather than as a series of established differences.

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("Plasmin Open-label Treatment Group A", "Plasmin Open-label Treatment Group B", "Plasmin Open-label Treatment Group C", "Plasmin Open-label Treatment Group D", "Plasminogen Activator Blinded Group E", "PA Placebo Blinded Treatment Arm F")
n      <- c(16, 19, 21, 19, 9, 5)
events <- c(7, 9, 17, 9, 8, 2)
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  Plasmin Open-label Treatment Group A  16  7  43.8  19.8  70.1  23.1  66.8  23.0  67.1
ARM  Plasmin Open-label Treatment Group B  19  9  47.4  24.4  71.1  27.3  68.3  27.2  68.5
ARM  Plasmin Open-label Treatment Group C  21  17  81.0  58.1  94.6  60.0  92.3  59.7  92.2
ARM  Plasmin Open-label Treatment Group D  19  9  47.4  24.4  71.1  27.3  68.3  27.2  68.5
ARM  Plasminogen Activator Blinded Group E  9  8  88.9  51.8  99.7  56.5  98.0  55.5  97.5
ARM  PA Placebo Blinded Treatment Arm F  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7

11. Multiplicity, Missing Data and Analysis Populations

The study had multiple plasmin regimens as well as a plasminogen activator group and a placebo group. A broad set of possible pairwise comparisons can create a multiplicity problem: the more comparisons considered, the greater the opportunity for chance variation to produce an apparently striking finding. The registry record does not report which comparisons were prespecified as primary, whether any adjustment for multiple testing was planned, or whether analyses were exploratory or confirmatory. It reports no outcome analyses in the posted record, so there are no reported p-values or multiplicity-adjusted results to interpret.

Missing or excluded endpoint assessments are also relevant. For groups A-D, G, and H, 8 subjects were excluded because an end-of-treatment arteriogram was missing or not read, or because they did not receive at least 90% of the dose. For groups I and J, 11 subjects were excluded for balloon occlusion catheter insertion or inflation issues or a missing arteriogram. The record notes that one participant in group F was not dosed and that 4 subjects were excluded, but the reason text is truncated. A complete explanation of the population used for every analysis is not reported in the registry record.

In general, an intention-to-treat analysis retains participants in their randomized groups, while an evaluable-participant analysis may omit those without usable endpoint data. The registry record does not state that the primary results follow an intention-to-treat approach, nor does it report a missing-data method or sensitivity analysis. It is therefore not possible to assess from the posted record how the exclusions affected the endpoint proportions, or whether the same conclusions would follow under alternative assumptions about missing outcomes.

The record also does not report interim analyses, a statistical analysis plan, or a sample-size justification. These omissions limit assessment of whether the endpoint populations, comparisons, and methods were fully prespecified.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: peripheral ischaemia (33.3%), peripheral embolism (20.0%), ischaemia (14.3%), shock haemorrhagic (11.1%), post procedural haematoma (11.1%).

The safety results list the number of participants at risk and the number affected by serious adverse events and other adverse events in each group. These are counts, not adjusted comparisons between treatments. For serious adverse events, the posted counts were 10 of 20 in group A, 4 of 20 in group B, 6 of 22 in group C, and 4 of 20 in group D. The corresponding counts were 2 of 9 in the plasminogen activator group, 5 of 9 in the placebo group, 4 of 13 in group G, 3 of 12 in group H, 7 of 21 in group I, 2 of 17 in group J, and 0 of 6 in group M.

The at-risk counts differ across groups, so raw counts should not be compared as though the groups were equally sized. The record does not report uncertainty intervals or formal statistical comparisons for these safety counts. A count of zero in a group does not establish that the event cannot occur, particularly where the at-risk group is small. In addition, deaths are not reported in the safety data available for this analysis; their status is not reported in the registry record.

Serious adverse-event terms listed most frequently include peripheral ischaemia at 33.3%, peripheral embolism at 20.0%, and ischaemia at 14.3%. Shock haemorrhagic, post procedural haematoma, and multi-organ failure are each listed at 11.1%. The record does not give enough context to interpret these terms as comparative risks by assigned arm. These figures describe reported safety events; they do not establish that an intervention caused an event or that groups differ in safety.

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

The results document a range of observed proportions meeting the angiographic threshold across the study’s treatment groups. They also document serious and other adverse-event counts by group. Together, these are descriptive findings from a randomized Phase 2 study evaluating different intra-thrombus plasmin delivery regimens alongside blinded plasminogen activator and placebo groups.

The posted endpoint percentages do not establish that a particular plasmin regimen is more effective than another, or that it is superior to either control. The registry record does not report formal comparisons, confidence intervals, p-values, or an adjusted analysis for the primary endpoint. Differences between the percentages could reflect true differences, random variation, or a combination; their relative contributions cannot be quantified from the posted summaries alone.

Nor can observed differences be attributed to one regimen feature in isolation. The plasmin groups varied in dose, pulsing, infusion duration and rate, and use of a balloon occlusion catheter. The design therefore describes outcomes under combinations of delivery procedures. A causal conclusion about the effect of any single feature would require an analysis capable of separating that feature from the other differences.

The endpoint is an arteriographic threshold measured at the end of treatment, with timing that differed among groups. It does not by itself describe longer-term outcomes, patient experience, or the overall balance of benefits and harms. The registry record’s safety counts are also descriptive, with no reported inferential comparisons and no deaths reported in the available safety results.

Interpretation is further limited by endpoint exclusions and incomplete population details. Missing or unreadable arteriograms, dose receipt, and catheter issues affected who was included in some group summaries. Since the full analysis population and handling of missing data are not reported in the registry record, the posted percentages cannot be assumed to represent all randomized participants. The results are most appropriately read as group-level summaries, not as definitive proof of a treatment effect or a clinical recommendation.

14. Why This Trial Matters Statistically

Statistically, this trial is notable for comparing a range of delivery regimens rather than testing a single simple treatment contrast. The plasmin arms varied in infusion duration and rate, pulsing, catheter use, and, for group M, dose. Such a design can describe what happened under each regimen, but makes it difficult to identify which individual delivery feature accounts for a difference in outcome.

The posted endpoint percentages also illustrate why denominators and uncertainty matter. The groups have different endpoint counts, including small counts in the controls and some plasmin arms. A group percentage is a point estimate; without an interval or inferential comparison, apparent differences in the percentages should not be read as precise evidence of differences in the underlying response probabilities.

Another important statistical issue is the distinction between randomized enrollment and the population contributing to an endpoint. The record describes post-randomization exclusions related to arteriogram availability, dose received, and catheter procedures. Such exclusions can affect interpretation, particularly when their occurrence varies by arm. The incomplete description of the endpoint population and absence of a reported missing-data analysis prevent a clear assessment of this issue.

Finally, multiple arms create many potential comparisons. Without a stated hierarchy of comparisons or multiplicity procedure, a reader cannot know which differences were intended to be confirmatory. The record’s lack of reported analyses means the results remain descriptive, even though the trial was randomized. This is a useful distinction: randomization is a design feature, while the strength of statistical conclusions also depends on prespecified contrasts, adequate analysis, uncertainty estimates, and transparent handling of missing outcomes.

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 primary endpoint results are posted as percentages with group counts, but the registry record does not report confidence intervals, hypothesis tests, effect estimates for between-group contrasts, or adjustment for the many possible comparisons. This prevents an assessment of statistical precision and makes formal ranking of regimens unsupported by the posted results.

The endpoint population description is incomplete. The record reports exclusions related to arteriogram availability, dose receipt, and balloon occlusion catheter procedures, but the full text defining the analyzed population is truncated. It does not state whether analyses retained participants in their randomized groups, how missing outcomes were handled, or whether sensitivity analyses were performed.

Several delivery features varied across plasmin groups, including infusion duration and rate, use of a proximal pulse, catheter use, and dose. Therefore, group-level differences cannot isolate the contribution of one feature. The record also does not explain why the endpoint timeframe lists some plasmin groups but not the blinded control groups.

Although the trial is identified as randomized, the method of sequence generation and allocation concealment is not reported in the registry record. The plasmin regimens were open-label, and the record does not say whether arteriogram readers were blinded. It also does not report baseline characteristics in the information available for this analysis.

The safety data are counts by group, with no reported inferential comparisons or uncertainty intervals. Deaths are not reported in the available safety results. The protocol’s statistical analysis plan, sample-size justification, interim analyses, and multiplicity approach are not reported in the registry record. These limitations constrain interpretation of both efficacy and safety summaries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Intra-thrombus Plasmin (Human) In Acute Peripheral Arterial Occlusion — NCT01222117.
• Registry record last updated 2017-01-16; status last verified 2016-11.
• Results first posted 2016-05-30.
• 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

This completed Phase 2 randomized, parallel-group study enrolled 174 participants with acute peripheral arterial occlusion. It evaluated several open-label intra-thrombus plasmin regimens and included blinded plasminogen activator and placebo groups. The primary endpoint was the proportion with more than 50% thrombolysis at the end of treatment compared with baseline by arteriography.

Posted endpoint proportions varied across groups, but the registry record reports no formal analyses, confidence intervals, or tests of between-group differences. It also describes endpoint exclusions and provides group-level adverse-event counts. The available record does not report a complete analysis-population definition, a missing-data approach, a multiplicity plan, or a statistical analysis plan. The results are therefore descriptive and do not establish comparative effects or isolate the influence of individual delivery features.