CLOTBUST Hands-Free: A Phase I/II Pilot Safety Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CLOTBUST Hands-Free: A Phase I/II Pilot Safety Trial (NCT01240356), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants in Phase I Group With Blood-brain-barrier Disruption (BBB) as Measured by MRI of the Brain.

2. Clinical Question

The trial asked whether a hands-free transcranial Doppler ultrasound system could be used safely in healthy volunteers and ischemic stroke patients. The primary safety question focused on whether the system was associated with blood-brain-barrier disruption detected by brain MRI in the Phase I group. The registry describes MRI assessment 2-3 hours after treatment, with scans performed before and after ultrasound in healthy volunteers.

The Phase I group consisted of healthy volunteers without a history of Central Nervous System Disease. They received continuous hands-free 2-MHz transcranial Doppler ultrasound for 2-hours. The Phase II group consisted of ischemic stroke patients presenting between 0-3 hours, who received continuous hands-free 2-MHz ultrasound to the intracranial vessels for 2-hours. The registry also lists outcomes concerning adverse events, arterial recanalization, neurological worsening, and excellent outcome.

This is a safety-focused question, not a randomized comparison of ultrasound against a control treatment. The registry categorizes the study as non-randomized and single-group, and reports no masking. It describes the two participant groups separately, but they differ in health status and treatment context; they should not be read as like-for-like comparison groups.

The record does not report the number of Phase I participants with blood-brain-barrier disruption. It also does not report results for the listed Phase II outcomes. Consequently, the registry description identifies what investigators intended to assess, but does not establish the observed primary endpoint result or the precision of an estimate. The results available in the record are limited to the posted adverse-event figures.

3. Trial Design

NCT01240356 is registered as a completed Phase I/II pilot safety trial sponsored by The University of Texas Health Science Center, Houston. The registry lists an enrollment of 35, a start date of 2008-12, and a primary completion date of 2013-10. The design is categorized as non-randomized, with no masking and a single-group model. The record describes a Phase I healthy-volunteer group and a Phase II ischemic-stroke group; those groups have different populations and are not a randomized treatment-versus-control comparison.

In Phase I, healthy volunteers without a history of Central Nervous System Disease received continuous hands-free 2-MHz transcranial Doppler ultrasound for 2-hours. Brain MRI with gadolinium was performed before and after the ultrasound. The primary outcome was the number of participants in this group with blood-brain-barrier disruption measured by MRI of the brain, assessed 2-3 hours after treatment.

In Phase II, ischemic stroke patients presenting between 0-3 hours received continuous hands-free 2-MHz transcranial Doppler ultrasound to the intracranial vessels for 2-hours. The registry lists secondary outcomes for adverse events in Phase I, arterial recanalization, neurological worsening determined by the NIH Stroke Scale, and excellent outcome measured by the modified Rankin Scale. These listed outcomes describe planned assessments; their results are not reported in the registry record.

The registry does not report a detailed statistical analysis plan, the rationale for the enrollment target, or how participants were assigned to the two phases beyond the descriptions of the groups. The completed status indicates the trial is recorded as completed, but it does not supply the missing primary endpoint result. Since allocation was not randomized and there was no masked comparison, between-group differences would not isolate an ultrasound effect.

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

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 in Phase I Group With Blood-brain-barrier Disruption (BBB) as Measured by MRI of the Brain, measured over 2-3 hours after treatment.

The primary endpoint is the number of participants in the Phase I group with blood-brain-barrier disruption detected by brain MRI. The registry describes MRI imaging as a way to assess whether the hands-free transcranial Doppler system resulted in blood-brain-barrier disruption or deterioration in permeability. The assessment timeframe is 2-3 hours after treatment. The Phase I volunteers had brain MRI with gadolinium before and after continuous ultrasound treatment.

As a safety endpoint, this measure addresses a potential imaging change following exposure to the device. A count of affected participants can convey how many people in the assessed group met the outcome definition. To interpret that count fully, readers also need the number assessed, the criteria used to classify disruption, and information about missing or unevaluable scans. The registry record does not report the observed endpoint count, the operational MRI threshold, or the handling of scans that could not be assessed.

General statistical explanation: a binary event endpoint records whether each participant did or did not meet a specified criterion. The event count is meaningful only alongside its denominator and a clear outcome definition. An estimate of the event proportion and its confidence interval would describe the observed frequency and its statistical precision, but neither is reported for this primary outcome in the registry record. The endpoint therefore identifies the intended safety assessment, while the posted record does not permit a numerical conclusion about its result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: an event count is a direct summary of how many participants met a binary outcome definition. For a safety endpoint such as blood-brain-barrier disruption, the count needs a denominator: the number of participants who were evaluated for that outcome. A count without an assessment denominator does not show the frequency among all enrolled participants, nor does it indicate how precise an estimate would be. The registry record does not report the primary endpoint count or its denominator.

What does an event count convey?

For a binary outcome, each participant is classified according to whether the event occurred. A count can be useful for describing the observed data, particularly when the outcome is uncommon, but it does not by itself establish risk or causation. An event proportion expresses the count relative to the participants assessed. A confidence interval around that proportion reflects uncertainty arising from the finite sample, under the assumptions of the interval method. A narrow interval indicates greater precision than a wide interval, but neither an interval nor a point estimate is reported for the primary outcome in this registry record.

The registry does provide adverse-event counts in the Phase I and Phase II groups. Those are descriptive summaries, and the denominators listed for adverse events do not necessarily establish how many participants had complete data for every secondary endpoint. The record does not report participant-level event detail, whether individuals had more than one event, or the duration and completeness of event surveillance. Those details matter when interpreting event counts and when comparing event categories.

Why does the design matter for interpretation?

General statistical explanation: random allocation can help create comparable groups at baseline, while masking can reduce certain kinds of assessment or reporting bias. Neither feature is recorded for this trial: allocation is listed as non-randomized and masking as none. The registry categorizes the design as single-group and also describes separate Phase I and Phase II cohorts. The healthy volunteers and stroke patients differ by population and clinical context, so the groups do not provide a like-for-like comparison. A difference in observed event counts between them cannot be attributed to the device on the basis of this design description.

The Phase I endpoint is specifically an MRI finding in healthy volunteers, whereas several listed Phase II outcomes concern patients with ischemic stroke. These endpoints address different questions and populations. The record does not report a control group receiving no ultrasound or another intervention, and it does not state that outcome assessors were masked. A within-person MRI comparison before and after treatment may describe change over time, but the registry does not report a statistical analysis of those scans or the criteria used to classify a change as blood-brain-barrier disruption.

What can a confidence interval add?

General statistical explanation: a confidence interval describes a range of values compatible with the observed data and the statistical model used. It is not a guarantee that the true value lies in the interval, nor does it remove limitations in study design or data collection. For a small safety cohort, uncertainty can remain substantial even when few events are observed. The record does not report a confidence interval for the primary endpoint or the adverse-event counts, so the precision of those observations cannot be quantified from the registry entries.

Interpretation also depends on how outcomes are defined and assessed. For MRI, the threshold for blood-brain-barrier disruption, image-reading procedures, and handling of equivocal scans would affect classification. For neurological worsening and clinical outcomes, the assessment schedule and missing assessments could matter. Those procedures are not reported in the registry record. They should not be reconstructed from the outcome labels alone.

How should planning calculations be read?

The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not a report of the trial's design justification. A planning calculation describes the size of a hypothetical future study under specified assumptions; it does not show that the current trial had a particular probability of detecting an effect.

Those assumptions also do not match a randomized, like-for-like comparison in this trial. The registry characterizes the study as non-randomized and single-group, and cautions that the arms are not a control comparison. A calculation based on equal allocation between two arms should therefore be read as a hypothetical planning exercise, not as a direct description of the actual design. The record does not report the protocol's sample-size justification or enough observed primary endpoint information to independently assess a planning effect.

What analysis details remain unknown?

The registry lists no statistical analyses. It does not report an analysis model, a prespecified significance test for the primary endpoint, a confidence-interval method, adjustment for multiple outcomes, or an analysis population definition. It also does not report missing-data procedures, the number of participants with evaluable MRI scans, or whether any participants were excluded from an outcome analysis. These omissions limit reproducibility and make it difficult to distinguish planned analyses from descriptive summaries.

General statistical explanation: for a binary endpoint, methods should account for the number assessed and the event count, and their assumptions should fit the study design. For a single-group safety endpoint, an estimate of the event frequency with an uncertainty interval may be more directly interpretable than a comparison between noncomparable cohorts. But no primary estimate is available, and the registry does not identify which method was used. Statistical methods cannot compensate for an unreported outcome definition or incomplete accounting of participants.

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("Phase I")
n      <- c(15)
events <- c(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  Phase I  15  0  0.0  0.0  21.8  0.0  20.4  0.2  20.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary MRI safety outcome and several secondary outcomes, including adverse events, arterial recanalization, neurological worsening, and excellent outcome. When a study assesses multiple outcomes, multiplicity can affect how readers interpret statistical tests: repeated testing can increase the chance of at least one apparently notable result under specified assumptions. General statistical explanation: prespecifying a primary outcome and describing any adjustment or hierarchy helps clarify which results are confirmatory and which are exploratory.

The registry record does not report a multiplicity strategy, an outcome hierarchy beyond identifying the primary endpoint, or statistical analyses for the listed outcomes. It also does not report p-values or confidence intervals for those outcomes. Without those details, the secondary outcomes should be understood as listed assessments rather than as a set of established findings.

The record does not report missing-data rules, analysis populations, or the number of participants with evaluable data for the primary MRI measure. Nor does it state how participants with incomplete follow-up or unavailable assessments were handled. Missingness can affect interpretation if the participants with observed outcomes differ from those without observed outcomes; this is a general statistical concern, not a finding established by the record.

The posted adverse-event denominators describe participants listed at risk for those event summaries, but the record does not establish that those denominators apply to every outcome. No intention-to-treat, per-protocol, or safety-population definition is reported. The absence of these details means that the completeness of the outcome analyses and the treatment of missing observations cannot be assessed.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cerebral edema (20.0%), pneumonia/respiratory failure (20.0%), death (15.0%), intracranial hemohhrage secondary to bacterial endocarditis (5.0%), sepsis (5.0%).

The registry lists serious and other adverse-event counts separately for the two groups. In Phase I, 15 healthy volunteers were listed at risk for serious adverse events, with 0 affected; 15 were listed at risk for other adverse events, with 0 affected. In Phase II, 20 ischemic stroke patients were listed at risk for serious adverse events, with 9 affected; 20 were listed at risk for other adverse events, with 19 affected. These are counts reported by the registry and should be read as descriptive safety information.

The record also lists serious-event terms and percentages: Cerebral edema, 20.0%; Pneumonia/respiratory failure, 20.0%; Death, 15.0%; Intracranial hemohhrage secondary to bacterial endocarditis, 5.0%; Sepsis, 5.0%; and Stroke progression/Nuero-worsening, 5.0%. The registry does not explain whether participants could contribute to multiple terms, how the percentages were calculated, or how terms were adjudicated. The dedicated deaths values are not reported.

Because the groups are not randomized or clinically comparable, these figures do not estimate a treatment-related difference. The registry counts alone do not establish whether an event was caused by ultrasound, by the underlying condition, or by another circumstance. They describe what is recorded, not a causal safety effect.

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

The registry record documents a completed pilot safety trial of hands-free 2-MHz transcranial Doppler ultrasound in healthy volunteers and ischemic stroke patients. It specifies that Phase I participants underwent MRI assessment before and after ultrasound and identifies blood-brain-barrier disruption as the primary endpoint. It also records adverse-event counts for both groups and lists additional outcomes for the stroke-patient group.

The record does not report the primary endpoint result. It therefore cannot establish how many Phase I participants had blood-brain-barrier disruption, how frequent the finding was among those assessed, or how precisely that frequency was estimated. The listed secondary outcomes also lack reported results. Although adverse-event counts are present, they are descriptive and do not support a causal conclusion about the device.

This interpretation is constrained by the study design. The registry lists non-randomized allocation, no masking, and a single-group model. The two described cohorts differ substantially in population and context, and are explicitly not a like-for-like control comparison. Their event counts should not be treated as evidence that one group had greater or lesser risk because of treatment.

General statistical explanation: a pilot study can contribute information about feasibility, outcome measurement, and the range of events observed, but the strength of its conclusions depends on the design, the completeness of reporting, and the precision of the estimates. The registry does not report an analysis plan, confidence intervals, or a sample-size justification. No efficacy conclusion follows from the listed outcomes alone. The record supports describing the study's intended safety assessment and its posted adverse-event figures, while leaving the primary endpoint and the statistical uncertainty unresolved.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the difference between a stated safety objective and a reported endpoint result. The registry identifies an MRI-based primary outcome, its target population, and its assessment timeframe. Yet the numerical primary result is not reported. Without an event count, denominator, and uncertainty estimate, readers cannot quantify the observed frequency of the primary safety finding or its precision.

The study also demonstrates why group labels do not automatically create a valid comparison. The registry describes healthy volunteers in Phase I and ischemic stroke patients in Phase II, with non-randomized allocation, no masking, and a single-group model. These are different populations rather than interchangeable treatment groups. The adverse-event counts can be described, but a contrast between them would not isolate the effect of ultrasound.

Another statistical issue is the distinction between observed findings and planning calculations. A sample-size illustration based on a hypothetical effect and allocation assumptions can help describe a future design, but it is not evidence about the study's observed power or proof that the completed trial could answer its primary question. The registry does not report the trial's sample-size justification or statistical analysis plan.

For clinical researchers, the record underscores the value of reporting outcome definitions, assessment denominators, analysis populations, missing-data handling, and uncertainty intervals alongside event counts. Those details allow readers to understand what was measured, who contributed data, and how much precision the results support. Here, the posted safety counts are informative as descriptive entries, while the missing primary result and analysis details set clear limits on interpretation.

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 limitation for interpreting this trial is that the registry record does not report the primary outcome count for blood-brain-barrier disruption. It does not provide the number of participants with evaluable MRI scans, the event definition or imaging threshold, or an uncertainty estimate. Thus, the intended primary safety assessment cannot be quantified from the registry record.

The design is non-randomized, unmasked, and categorized as single-group. The Phase I healthy volunteers and Phase II ischemic stroke patients are not a like-for-like comparison. Differences in their adverse-event counts cannot be attributed to the ultrasound device. The registry does not describe a concurrent control group, and it does not report how participants entered each phase.

Important reporting details are also absent: the protocol's sample-size justification, statistical analysis plan, analysis populations, missing-data procedures, and multiplicity strategy are not reported in the registry record. Outcome definitions and assessment procedures for the secondary measures are not fully described. The record lists adverse-event counts and selected serious-event terms, but does not explain overlap among terms, event adjudication, or the calculation basis for the listed percentages. Dedicated deaths counts are not reported.

Finally, the registry lists secondary outcome measures without corresponding results and records no statistical analyses. The completion status and enrollment entry do not resolve these gaps. These limitations concern the information available in the registry record; they do not establish that an unreported result was favorable, unfavorable, or absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: CLOTBUST Hands-Free: A Phase I/II Pilot Safety Trial — NCT01240356.
• Registry record last updated 2016-05-23; status last verified 2016-05.
• Results first posted 2016-05-23.
• 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

NCT01240356 is a completed Phase I/II pilot safety trial sponsored by The University of Texas Health Science Center, Houston. The registry lists enrollment of 35, a start date of 2008-12, and a primary completion date of 2013-10. The design is categorized as non-randomized, unmasked, and single-group.

Phase I healthy volunteers received continuous hands-free 2-MHz transcranial Doppler ultrasound for 2-hours and underwent MRI with gadolinium before and after treatment. The primary endpoint was the number with blood-brain-barrier disruption measured by MRI 2-3 hours after treatment. Phase II ischemic stroke patients presenting between 0-3 hours received continuous ultrasound for 2-hours. The registry lists additional safety and clinical outcomes.

The primary endpoint result and statistical analyses are not reported in the registry record. Adverse-event counts are recorded for each group, but the groups are not a like-for-like control comparison. The posted information supports descriptive reporting only, not a causal treatment comparison.