Ultrasound Liver Intraoperative Imaging With SonoVue®: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ultrasound Liver Intraoperative Imaging With SonoVue® (NCT01880554), a na na study. The primary outcome is Clinical Utility of Intraoperative Contrast Ultrasound in the Surgery of Colorectal Cancer Liver Metastases..

2. Clinical Question

3. Trial Design

This is a multicenter phase II study, described in the registry summary as using a two-stage Simon design. The record lists the study as completed and gives enrollment as 68. Its allocation field is NA, its masking field is NONE, and its model is SINGLE GROUP. These features describe a study without a randomized, masked, parallel-arm comparison. The intervention listing is contrast-enhanced intraoperative ultrasound.

The registry describes a planning design with a maximum tolerated futility rate of 5%, an expected minimum utility rate of 15%, Type I error of 10%, and power of 85%. It states that 52 eligible and evaluable patients were required, with 25 in the first stage. These are design assumptions and planned counts, not the reported endpoint result. The record does not give the final number eligible and evaluable for the primary endpoint, nor does it explain how that population relates to the enrollment field of 68.

The first-stage description is incomplete: it begins to state a stopping rule but does not give the complete rule. The remaining decision thresholds and the full second-stage procedure are not reported in the registry record. The start date is 2011-06 and primary completion is 2016-09. Further details of the trial conduct, including the reasons for the difference between enrollment and the planned evaluable population, 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: We used a 2-stage Simon's design with the following assumptions: * maximum tolerated futility rate: 5%, * expected minimum utility rate: 15%, * Type I error of 10%, * power of 85%. Thus, 52 eligible and evaluable patients were required (25 in the first stage). First stage: stop, if CE-IOUS is not deemed clinically useful for at least one patient (4.0%). Second stage: CE-IOUS clinically useful if the planned surgical procedure is modified and justified for 5 or more patients (9.6%).

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 Clinical Utility of Intraoperative Contrast Ultrasound in the Surgery of Colorectal Cancer Liver Metastases., measured over At time of surgery.

The primary endpoint is the percentage of patients for whom the surgical procedure envisaged after CE-IOUS differs from the procedure envisaged after conventional intraoperative ultrasound and the CE-IOUS-based procedure is judged justified. Both conditions must hold for a patient to count as meeting the endpoint. A change without justification is not sufficient under the stated definition.

The endpoint is assessed at the time of surgery and is intended to capture clinical utility in terms of a procedural decision, rather than simply whether contrast imaging detects a lesion. The registry lists the measure as a percentage of patients and specifies a 95% confidence interval. That interval would communicate the uncertainty around the estimated percentage; it would not establish that every observed change was appropriate in other settings.

The endpoint is distinct from the listed secondary outcomes, which concern patients who received preoperative chemotherapy, lesion detection, technical arrangements, and lesion characterisation. Although the primary endpoint definition and intended reporting format are recorded, its observed percentage and confidence interval are not reported in the registry record. The number of patients who met both endpoint conditions is also not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical design described in the registry is a two-stage Simon phase II design. In general, a two-stage design evaluates an outcome after an initial group of participants and may stop early for futility before proceeding to a later stage. This structure can limit continued enrollment when early results do not meet a prespecified decision rule. The registry gives some design assumptions and counts, but the full stopping rule and second-stage decision details are not reported in the registry record.

The stated assumptions are a maximum tolerated futility rate of 5%, an expected minimum utility rate of 15%, Type I error of 10%, and power of 85%. These figures describe the planning framework, not the observed result. The record says 52 eligible and evaluable patients were required, with 25 in the first stage. It does not report whether the planned second-stage threshold was reached or how many patients were ultimately eligible and evaluable for the primary analysis. The enrollment field is 68; that does not by itself identify the analysis population.

What does the primary percentage represent?

The primary measure is a binary patient-level classification summarized as a percentage. A patient meets the stated definition when two conditions are both satisfied: the envisaged procedure after CE-IOUS differs from the one envisaged after conventional intraoperative ultrasound, and the CE-IOUS-based procedure is justified. The percentage would describe how often this defined outcome occurred among the patients included in the analysis. The registry record does not report the observed percentage or its denominator.

What would a confidence interval add?

The registry specifies a 95% confidence interval for the primary percentage. In general, a confidence interval gives a range of values compatible with the estimate under the chosen statistical procedure and its assumptions. A narrower interval indicates greater statistical precision than a wider interval, but the interval is not a guarantee that the true value lies within a particular range. Because neither the estimate nor its interval is reported in the registry record, the precision of the primary result cannot be judged.

How should the design shape interpretation?

A single-group design does not estimate a treatment contrast between randomized arms. In this study, the endpoint compares two envisaged procedures within the definition of a patient-level outcome, but the record does not describe a randomized allocation to conventional ultrasound versus CE-IOUS. General statistical interpretation should distinguish a within-patient procedural reference from a concurrent control group. The former can describe changes in planned procedures; it does not, on its own, isolate the effect of the imaging strategy on later clinical outcomes.

The Simon design’s error and power assumptions relate to its planned decision process and specified utility rates. They should not be interpreted as evidence that the study achieved a particular result. Power is a design property under assumptions, not a measure of the probability that a reported finding is true. The registry record does not report the final stage decision or the endpoint data required to assess the planned criterion.

What is the role of planning illustrations?

Any sample-size illustrations based on an observed effect are planning exercises, not observed power and not results from the trial’s own design. In general, such calculations ask how many participants per arm might be required under stated assumptions for a future comparison. They do not change the single-group design recorded for this study. The record’s illustration assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Those hypothetical assumptions should not be confused with the Simon design assumptions, which are stated separately.

For count outcomes in general, over-dispersion means that variability exceeds what a simple model assumes. It can make conventional uncertainty estimates too small if the model does not account for the extra variability. That general issue does not establish that over-dispersion occurred in this trial, and the registry record does not report a model-based analysis of the primary endpoint. Since the endpoint result and analysis details are absent, the suitability of any particular estimation method cannot be evaluated from the registry record.

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("Contrast-enhanced Intraoperative Ultrasound")
n      <- c(52)
events <- c(4)
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  Contrast-enhanced Intraoperative Ultrasound  52  4  7.7  2.1  18.5  3.0  18.2  3.1  18.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and four secondary outcomes: clinical utility among patients who received preoperative chemotherapy, lesion-level detection rate, technical arrangements for CE-IOUS, and lesion-level characterisation rate. When several outcomes are assessed, multiplicity can increase the chance of at least one apparently notable result if each is tested separately. In general, a prespecified testing hierarchy or adjustment can address that issue, but the registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or inferential results for these outcomes.

The registry records zero analysis entries. It does not report numerical results for the primary endpoint or the listed secondary outcomes. The analysis methods, handling of repeated or multiple lesions per patient, and any adjustment for clustering are not reported in the registry record. The record also does not report whether any interim analyses were conducted or whether the two-stage design’s interim decision rules were applied as planned.

Missing-data handling is not reported in the registry record. The endpoint’s analysis population, exclusions from analysis, missing endpoint counts, and the approach to incomplete observations are not specified. The design description refers to eligible and evaluable patients, but it does not provide the final number meeting that definition or define the analysis population in greater detail. Therefore, the extent and consequences of missing endpoint data cannot be assessed. The enrollment figure should not be treated as the denominator for the unreported endpoint estimate.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: peritonitis (3.7%), biliary fistula (3.7%), pleural effusion (3.7%), hypertension (1.9%), eventration (1.9%).

For the group labelled Contrast-enhanced Intraoperative Ultrasound, the registry lists 54 at risk for serious events and 11 affected in the serious-event fields. It also lists 54 at risk and 2 affected in the other-event fields. These are separate registry fields; they should not be combined or interpreted as mutually exclusive categories without further information. The registry record does not report the safety observation timeframe or additional detail on event ascertainment.

The listed serious-event terms include Peritonitis, Biliary fistula, and Pleural effusion, each with a reported percentage of 3.7%. Hypertension, Eventration, and Bile collection secondary to a biliary tract wound are each listed with a reported percentage of 1.9%. The record presents these terms and percentages but does not provide event-level descriptions or explain whether individuals could contribute to more than one term. The terms should not be added together or treated as a complete account of all events.

The deaths field is null. This does not establish that no deaths occurred; a death count is not reported in the registry record. These safety figures are not a comparison with another group, and they do not provide a basis for attributing events to the intervention.

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

The study’s central statistical question is whether contrast-enhanced intraoperative ultrasound is associated with a justified change in the envisaged surgical procedure, using the registry’s two-part endpoint definition. The registry describes how that outcome was intended to be measured and states that a percentage with a 95% confidence interval would be reported. The numerical estimate and interval are not reported in the registry record, so the frequency and precision of the endpoint remain unknown from this record.

The single-group design is relevant to what can be inferred. The conventional ultrasound procedure is used as a reference within the endpoint definition, while the study is not listed as a randomized comparison. A record of changed plans could address the stated procedural-utility question, but it would not by itself quantify a causal effect on later patient outcomes. The primary endpoint is about a justified change in a planned procedure, not a direct measure of survival, recurrence, or another clinical outcome; those outcomes are not described as the primary endpoint in this record.

The registry’s Simon design assumptions describe how the study was planned to assess utility and futility. They do not establish that the endpoint met its planned criterion. Without the observed endpoint result and the complete decision rule, the study’s final statistical decision cannot be reconstructed from the record. Likewise, enrollment and safety figures do not fill that gap.

The safety information has a separate role. It reports affected counts and selected serious-event terms for the intervention group, but provides no comparison group and does not report a death count. These entries describe what is recorded in the safety fields; they do not establish a causal relationship between the intervention and an event or quantify comparative safety.

Overall, the record supports a description of the question, design, endpoint definition, and some safety entries. It does not support a numerical conclusion about primary clinical utility. That distinction matters: an endpoint can be clearly defined while its observed estimate remains unavailable, and planning assumptions are not a substitute for outcome data.

14. Why This Trial Matters Statistically

This trial is statistically notable for using a two-stage phase II design to evaluate a patient-level clinical-utility outcome in surgical imaging. The endpoint is not simply whether the imaging procedure changes a plan. It requires both a change from the procedure envisaged after conventional intraoperative ultrasound and a judgment that the CE-IOUS-based procedure is justified. That joint definition makes the intended outcome more specific than a detection count alone.

The design also illustrates the difference between a planning framework and a reported result. The record gives futility and utility assumptions, error and power targets, and a planned evaluable population. Those features explain how the study was intended to proceed, but they cannot show whether the clinical-utility criterion was met. The incomplete description of the stage rules and the absence of the endpoint estimate limit reconstruction of the decision process.

The comparator distinction is important for statistical interpretation. Conventional intraoperative ultrasound serves as a reference in deciding whether the planned procedure changed, but the registry lists a single-group design rather than a randomized control comparison. That can support a descriptive account of changed and justified plans if results are available, but it does not supply the same kind of between-group estimate as a randomized design.

Finally, the record separates the endpoint question from safety reporting. Serious-event counts and selected terms are present, while the primary clinical-utility percentage is absent. Reading each type of information according to its purpose prevents safety fields, enrollment, or design assumptions from being mistaken for evidence about the primary endpoint.

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 most consequential limitation of the registry record is that it does not report the primary endpoint estimate, its 95% confidence interval, or the number of patients meeting the endpoint definition. The record therefore does not permit assessment of the observed clinical-utility rate or its precision. It also does not report the final eligible and evaluable analysis population, so the relevant denominator is unavailable.

The design description is incomplete. Although it identifies a two-stage Simon design and gives the first-stage planned count, the stopping rule is truncated and the remaining stage criteria are not reported in the registry record. The final stage reached and the decision under the design are also not reported. The record does not explain how the enrollment figure of 68 relates to the stated requirement for 52 eligible and evaluable patients.

Allocation is listed as NA, masking as NONE, and the model as single group. The endpoint uses conventional intraoperative ultrasound as a procedural reference, but this is not a randomized control arm. The registry record does not report additional design information that would permit a comparative causal analysis.

Analysis methods, multiplicity handling, missing-data procedures, and the analysis population are not reported in the registry record. The safety entries give counts and selected terms but do not report the observation timeframe, event-level detail, or a death count. These omissions limit interpretation of both efficacy-related and safety information recorded for the study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ultrasound Liver Intraoperative Imaging With SonoVue® — NCT01880554.
• Registry record last updated 2025-09-03; status last verified 2021-04.
• Results first posted 2021-05-18.
• 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

The registry record describes NCT01880554, titled Ultrasound Liver Intraoperative Imaging With SonoVue®, as a completed multicenter phase II study of contrast-enhanced intraoperative ultrasound in surgery for colorectal liver metastases. It lists a single-group model, no masking, enrollment of 68, a start date of 2011-06, and primary completion in 2016-09.

The primary endpoint is the percentage of patients with a changed and justified envisaged surgical procedure after CE-IOUS compared with conventional intraoperative ultrasound, assessed at surgery. The record describes a two-stage Simon design and reports planning assumptions, but the primary endpoint result and confidence interval are not reported in the registry record. Safety fields list 11 serious-event affected and 2 other-event affected among 54 at risk in each field; the death count is not reported.