This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for CEUS Evaluation of Hypoxic Ischemic Injury (NCT03549520), a na phase 3 study. The primary outcome is Detection of Brain Perfusion Abnormalities Using Contrast-enhanced Ultrasound.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03549520 |
| Phase | Phase 3 |
| Condition | Hypoxic-Ischemic Encephalopathy, Brain Ischemia Hypoxia |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 1 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Children's Hospital of Philadelphia |
| Results posted | Yes |
2. Clinical Question
Population
Neonates and infants with suspected or diagnosed hypoxic ischemic injury, or considered at risk of HII. The planned comparison also referred to normal subjects whose imaging and clinical evaluation did not show HII.
Intervention
Contrast-enhanced ultrasonography, using intravenous sulfur hexafluoride lipid-type A microspheres before the CEUS examination. The investigational scan was described as separate from clinically indicated conventional ultrasound.
Comparator
The intended comparison was between normal subjects and HII patients. The registry record states that one subject was enrolled and that this subject had HII confirmed by MRI, so the comparison could not be made.
Primary question
Can CEUS detect brain perfusion abnormalities during an examination lasting up to 15 minutes, and how does perfusion compare between normal subjects and patients with HII?
The study addresses whether bedside CEUS can characterize brain perfusion in neonates and infants with hypoxic ischemic injury. The registry describes a clinical context in which rapid, non-invasive imaging with spatial resolution and tissue contrast is sought, and identifies CEUS as an investigational approach for bedside monitoring. Scans were planned at two time points: when HII was first suspected or diagnosed, and at the time of MRI.
The primary endpoint was framed as a comparison of perfusion between two clinical groups, rather than as a comparison of randomized treatment arms. Because the single enrolled subject had HII confirmed by MRI, there was no enrolled normal subject against whom to compare the perfusion finding. The registry record therefore states that no comparison was possible. It does not report a comparative estimate of perfusion, nor does it establish how well CEUS distinguishes HII from normal findings.
3. Trial Design
This was a completed Phase 3 study registered as a single-group study, with allocation listed as not applicable and masking listed as none. The study was conducted at one site, The Children's Hospital of Philadelphia. The intervention was contrast-enhanced ultrasonography following intravenous administration of sulfur hexafluoride lipid-type A microspheres. The registry describes investigational CEUS scans as separate from clinically indicated conventional ultrasound.
The study dates in the registry are a start date of 2020-12-01 and a primary completion date of 2024-05-07. The study status is completed. Although the record describes an intended comparison between normal subjects and patients with HII, it does not describe a randomized, controlled, or masked comparison. It reports that one subject was enrolled, and that the subject had HII confirmed by MRI. The registry explicitly states that no comparison was possible.
The brief summary describes CEUS scanning at the time HII was first suspected or diagnosed and again at the time of MRI. The CEUS examination was interpreted by the sponsor-investigator. The stated expected recruitment was up to 100 subjects per year for up to two years, with total enrollment described as up to 200 subjects. The actual enrollment reported in the registry is one subject. The record does not explain why actual enrollment differed from the stated expectation.
A single-group structure can support descriptive observations about the enrolled participant, but it does not by itself provide a concurrent control group. In this study, the stated primary comparison required observations from both normal subjects and HII patients. Since only an HII patient was enrolled, the intended group comparison cannot be estimated from the reported enrollment.
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
| Stage | Brain Contrast-enhanced Ultrasonography |
|---|---|
| STARTED | 1 |
| COMPLETED | 1 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: One subject was enrolled, therefore, no comparison was possible. The patient presented with HII confirmed by MRI.
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: Low enrollment. Main reason was not fulfillment of inclusion/exclusion criteria, either for clinical instability and/or pulmonary insufficiency/hypertension.
| Characteristic | Unit | Brain Contrast-enhanced Ultrasonography |
|---|---|---|
| Participants analysed | 1 | |
| Age, Categorical: <=18 years | Participants | 1 |
| Age, Categorical: Between 18 and 65 years | Participants | 0 |
| Age, Categorical: >=65 years | Participants | 0 |
| Age, Continuous | Days | 14 (SD 0) |
| Sex: Female, Male: Female | Participants | 0 |
| Sex: Female, Male: Male | Participants | 1 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 |
| Race (NIH/OMB): White | Participants | 1 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Region of Enrollment: United States | participants | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Detection of Brain Perfusion Abnormalities Using Contrast-enhanced Ultrasound, measured over During contrast-enhanced ultrasound examination, up to 15 minutes..
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is titled detection of brain perfusion abnormalities using contrast-enhanced ultrasound. It is defined in participants and described as a number measure, with assessment during the CEUS examination, up to 15 minutes. The registry's description frames the endpoint as a comparison of brain perfusion between normal subjects and HII patients. It defines normal subjects as those with suspected or at-risk HII who turn out to be normal on imaging and clinical evaluation.
This type of endpoint is intended to address whether perfusion findings differ across the clinical categories relevant to the study question. A comparison could help characterize whether CEUS findings are associated with HII status in the studied population. In general, measuring a clinically meaningful imaging feature can help assess a diagnostic method, but a group comparison alone does not establish diagnostic accuracy unless the analysis and reference classification support that interpretation.
The registry record states that one subject was enrolled and that this subject had HII confirmed by MRI. It also states that no comparison was possible. Consequently, the endpoint does not yield a comparative result for normal subjects versus HII patients in this record. No numerical primary endpoint result, measure of uncertainty, or diagnostic performance estimate is reported in the registry record. The timeframe describes when the examination-level measure was to be assessed; it does not supply a result for the endpoint.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive fact is that the study enrolled one subject, who had HII confirmed by MRI. The registry record says directly that no comparison was possible. The primary question called for comparing brain perfusion in normal subjects with perfusion in HII patients, so the reported enrollment does not furnish the two groups needed for that comparison. As a result, the registry record does not provide an estimate of a difference between groups or a statistical test of that difference.
The primary endpoint is a count of participants with brain perfusion abnormalities assessed during CEUS, with the endpoint timeframe stated as up to 15 minutes. The record does not report a numerical primary endpoint result for that measure. It therefore does not support a claim about how often abnormalities were detected, how findings varied by HII status, or how precisely any such quantity was estimated. The fact that MRI confirmed HII in the enrolled subject describes that subject's clinical classification; it is not itself a comparison of CEUS findings between groups.
The study is listed as Phase 3 and completed, but these registration descriptors do not replace evidence from the stated endpoint. The study's design is single-group, with no masking and allocation listed as not applicable. These features are relevant because the primary question was comparative even though the registered structure was not a randomized, like-for-like control comparison. The registry's explicit statement that no comparison was possible is the appropriate boundary for interpreting the primary result.
The record reports no analyses. It also does not report a confidence interval, p-value, or other inferential statistic for the primary endpoint. Thus there is no reported statistical precision with which to judge a group contrast. General statistical principle: a confidence interval communicates uncertainty around an estimate; without a reported estimate and interval, the precision of a comparative effect cannot be assessed. The absence of a reported comparison should not be converted into evidence that the groups would be similar or different.
The study summary describes a planned scan at initial suspicion or diagnosis and another at MRI. However, the primary endpoint description does not report paired scan results or a numerical trajectory over time. The registry record also does not report the diagnostic-quality outcome results, despite listing a secondary outcome concerning participants with completed brain CEUS exams categorized by a diagnostic-quality scoring system.
Accordingly, the posted record documents the study's clinical question, design, enrollment, and the reason a comparison could not be made. It does not supply an estimate of CEUS performance for detecting HII-related perfusion abnormalities. These statements describe what is reported and what is absent; they are not a conclusion about the clinical utility of CEUS.
9. Statistical Methods Explained
What does a comparison require?
The primary endpoint was framed around differences in brain perfusion between normal subjects and HII patients. A comparative analysis requires observations representing both groups, together with a defined outcome measure for each participant. Here, the registry record says that one subject was enrolled, that the subject had HII confirmed by MRI, and that no comparison was possible. Without observations from normal subjects, a contrast between the groups cannot be estimated from the reported enrollment.
General statistical explanation: a group comparison estimates how an outcome differs across groups and quantifies uncertainty in that contrast. The outcome might be represented as a count, proportion, or another measure, depending on the prespecified endpoint and analysis. The registry lists the primary measure as a number of participants, but it does not report a numerical primary result or comparative analysis. It would therefore be inappropriate to derive a group effect from the information in the record.
What does the endpoint format mean?
The primary outcome is described as a number of participants, and the outcome type is participants with an event, recorded as counts. For a binary outcome, each participant is classified according to whether the event or finding is present. General statistical explanation: counts can describe how many participants meet a definition, while a proportion also relates that count to the number assessed. A count by itself does not establish a rate or probability unless the relevant denominator and outcome definition are available.
The registry's endpoint description refers to detection of brain perfusion abnormalities, but the record does not report a numerical count for this endpoint. It also does not provide the outcome-level classifications needed to reconstruct a result. No recalculated estimate is presented. In particular, no comparison, risk difference, ratio, or uncertainty interval should be inferred where the record states that no comparison was possible.
What can uncertainty measures tell a reader?
General statistical explanation: a confidence interval is a range of values compatible with the data and the assumptions of an analysis. Its width reflects statistical precision, with wider intervals indicating less precision. A p-value, when used under a specified test, describes how compatible the observed data are with a particular null model; it does not measure the probability that a clinical conclusion is true. Neither kind of statistic can remedy the absence of the groups or endpoint results required for the analysis.
The registry record reports zero analyses. It does not report a confidence interval, p-value, test statistic, or adjusted estimate for the primary endpoint. Thus, the comparative effect and its precision are not reported in the registry record. This is different from a result that is statistically inconclusive: no comparative estimate is reported to assess in the first place.
How should the study structure affect interpretation?
The study is listed as single-group, with allocation not applicable and masking none. General statistical explanation: random allocation, when used, can help make groups comparable with respect to measured and unmeasured factors, while masking can reduce the influence of knowledge about group assignment on measurement or interpretation. Those protections are not described as part of this record. More importantly for the stated primary question, the registry describes a comparison of clinical categories but reports no normal comparison group among those enrolled.
The CEUS examination was interpreted by the sponsor-investigator. The registry does not report an independent reader, a blinded reading procedure, or an assessment of agreement between readers. These methods are not reported in the registry record and should not be assumed. The record also does not report a prespecified threshold defining an abnormal perfusion finding or the method used to compare image findings with the MRI classification beyond identifying the enrolled subject as having HII confirmed by MRI.
How do planning illustrations differ from trial results?
The record describes sample-size assumptions for a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also states that the effect to detect is a stated fraction of the observed effect, and distinguishes participant-per-arm outputs from total-event outputs for time-to-event settings. These are planning assumptions, not evidence that the study used that design or achieved a particular power.
General statistical explanation: sample-size planning asks how much information a future study might need under specified assumptions about the effect and analysis. A planning calculation depends on those assumptions and is not an observed trial outcome. It is also not observed power. The record's actual study is single-group, and the primary comparison could not be made. The registry does not report a sample-size justification for the actual study, nor does it report that the planning assumptions were adopted as its protocol or analysis plan.
Over-dispersion is a general concern when count data vary more than an assumed statistical model expects; if ignored, uncertainty can be understated. The registry record does not report a count model, an over-dispersion assessment, or an analysis of count variability. Since no primary comparison is reported, it is not possible to evaluate whether such modeling choices affected an estimate.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists two outcome measures and identifies the detection of brain perfusion abnormalities using CEUS as the primary outcome. A secondary outcome concerns the number of participants with completed brain CEUS exams, categorized by a diagnostic-quality scoring system. The registry record does not report analyses for these outcomes. It does not report results for the diagnostic-quality outcome, a statistical analysis plan, or a stated approach to multiplicity.
General statistical explanation: multiplicity arises when multiple outcomes, time points, subgroups, or statistical tests are assessed. Without a defined approach, repeated testing can increase the chance of finding a result that appears noteworthy by chance. A prespecified hierarchy or adjustment can address some multiplicity concerns, but the record does not report such a plan. No adjustment method should be inferred.
The brief summary describes CEUS at two time points: when HII is first suspected or diagnosed and at the time of MRI. It does not report how those observations would be combined, whether one time point would be primary, or how repeated measures would be analyzed. Those analysis details are not reported in the registry record.
The registry record does not describe missing-data handling, exclusions, an analysis population, or whether all enrolled subjects contributed to each outcome. It reports one subject enrolled, but does not give a separate accounting of evaluable participants for the primary endpoint or secondary outcome. No imputation procedure or sensitivity analysis is reported. These omissions mean that missingness and analysis-population decisions cannot be assessed from the registry record; they should not be filled in by assumption.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Brain Contrast-enhanced Ultrasonography | 0 | 1 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Brain Contrast-enhanced Ultrasonography | 0 of 1 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Brain Contrast-enhanced Ultrasonography | 0 of 1 |
The adverse-event record lists a group titled Brain Contrast-enhanced Ultrasonography. For this group, the registry reports one participant at risk for serious adverse events and zero participants with serious adverse events. It also reports one participant at risk for other adverse events and zero participants with other adverse events. The recorded number of deaths is zero. No top serious adverse-event terms are listed.
These figures are counts from the registry record. They should be read in light of the reported enrollment of one subject and the limited information available in the record. A zero count means that no affected participant was recorded in the corresponding category; it does not establish that an event is impossible or that the intervention is free of risk. With only the registry counts reported, the frequency and uncertainty of uncommon harms cannot be characterized reliably.
The registry does not provide further details about how adverse events were defined, how long participants were monitored for safety, or whether events were assessed for relatedness to the contrast agent or procedure. Those details are not reported in the registry record. The listed counts therefore describe the posted safety categories, not a complete characterization of the safety profile.
12. What the Result Does, and Does Not, Mean
The record establishes that a completed study evaluated CEUS as a means of assessing brain perfusion in neonates and infants with suspected or diagnosed hypoxic ischemic injury. It identifies a primary question comparing normal subjects with HII patients, describes scans at two clinical time points, and reports that the enrolled subject had HII confirmed by MRI. These details describe the study's intent and the one subject's classification.
The record does not establish whether CEUS can distinguish HII from normal findings. One subject was enrolled, and the registry states that no comparison was possible. No numerical primary endpoint result, diagnostic performance measure, or comparative analysis is reported. The record therefore cannot support an estimate of sensitivity, specificity, or the difference in perfusion findings between clinical groups.
The study is listed as Phase 3 and completed, but those labels do not change the evidentiary limits of the reported results. A completed registration does not necessarily mean that every planned comparison was estimable or that results for every listed outcome are reported. In this case, the record documents that the intended group comparison could not be performed.
General statistical explanation: a study with very limited information cannot reliably distinguish a real pattern from random variation, and the absence of a detected or reported finding is not proof that no effect exists. Here, there is no reported group comparison to interpret as positive, negative, or inconclusive. The primary result is not a test showing that groups are alike; it is an unavailable comparison because the required groups were not represented in the enrollment.
The registry record also does not report the diagnostic-quality outcome result or inferential analyses. Consequently, the available information does not establish reproducibility, measurement precision, or performance across a broader population. These limits describe the reach of the posted evidence and do not determine how CEUS might perform in other studies.
13. Why This Trial Matters Statistically
This trial matters statistically because the clinical question and the enrolled study structure do not produce an analyzable comparison. The primary endpoint asks about perfusion differences between normal subjects and HII patients, while the registry lists a single-group study and reports one enrolled subject with HII confirmed by MRI. The record explicitly states that no comparison was possible. This makes the distinction between a planned question and an estimable result central to interpretation.
The case also illustrates why a study's phase label, completion status, and expected enrollment should not be substituted for the observed evidence. The registry describes an expectation of up to 100 subjects per year for up to two years, with enrollment up to 200, but reports actual enrollment of one subject. That contrast is important context, while the reason for the difference is not reported in the registry record.
General statistical explanation: an endpoint can be well motivated yet remain unanswered if the information needed to estimate it is unavailable. Precision depends on the observed data and study design, not simply on the intended sample size or a study label. Here, the record reports no analyses or numerical primary result, so readers cannot assess an estimated group effect or its uncertainty.
Finally, the registry separates the primary imaging question from a secondary measure of completed CEUS exams categorized by diagnostic quality. Neither outcome has a reported analysis in the record. This highlights the importance of reporting outcome results and analysis methods alongside the original clinical question. The statistical lesson is not a conclusion about the imaging technology, but a clear boundary: the registered question cannot be resolved by the reported enrollment and results.
14. 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 is the mismatch between the comparative primary question and the reported enrollment. The registry states that one subject was enrolled, with HII confirmed by MRI, and that no comparison was possible. As a result, the primary endpoint does not yield a contrast between normal subjects and HII patients.
The registry reports no analyses and no numerical primary outcome result. It also does not report results for the secondary outcome concerning completed brain CEUS exams and diagnostic-quality scoring. Confidence intervals, p-values, or other measures of uncertainty are not reported in the registry record. Readers therefore cannot assess the size or precision of a CEUS finding from the posted results.
The study summary describes two planned scan time points, but does not report paired results or how repeated observations were analyzed. The record does not report a prespecified abnormality threshold, a detailed reading protocol, an independent image review, or reader agreement. It identifies the sponsor-investigator as the CEUS interpreter, but does not describe further safeguards against interpretive bias.
The registry does not report missing-data procedures, analysis populations, a statistical analysis plan, or a multiplicity strategy. It also does not explain why actual enrollment was one despite the stated expectation of up to 200 subjects. These details are not reported in the registry record. The single-site setting is stated, but the record does not provide information that would allow readers to assess how representative the enrolled subject was of the broader population described by the study question.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: CEUS Evaluation of Hypoxic Ischemic Injury — NCT03549520.
- Registry record last updated 2025-05-14; status last verified 2025-05.
- Results first posted 2025-05-14.
- 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.
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18. Record Summary
NCT03549520, titled CEUS Evaluation of Hypoxic Ischemic Injury, is listed as a completed Phase 3, single-group study at The Children's Hospital of Philadelphia. It evaluated contrast-enhanced ultrasound with sulfur hexafluoride lipid-type A microspheres for brain perfusion assessment in neonates and infants with suspected or diagnosed HII. The registry lists no masking and allocation as not applicable.
The primary endpoint concerned detection of brain perfusion abnormalities and comparison of normal subjects with HII patients during CEUS, up to 15 minutes. The record reports one subject enrolled, with HII confirmed by MRI, and states that no comparison was possible. It lists a secondary diagnostic-quality outcome, but reports no analyses. The registry record does not report a numerical primary result or comparative estimate.
The study dates are 2020-12-01 and 2024-05-07 for start and primary completion, respectively. The record describes expected enrollment up to 200, while actual enrollment is one. The reason for this difference is not reported in the registry record.