Endothelin-1 and Cardiac Allograft Vasculopathy (CAV): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Endothelin-1 and Cardiac Allograft Vasculopathy (CAV) (NCT05373108), a na phase 4 study. The primary outcome is Macitentan: Nitroglycerin (NTG) Luminal Dilation Ratio as Proportion of Vasomotor Tone Attributable to Endothelin-1 (ET-1).

2. Clinical Question

The study addresses a physiological question in heart transplant recipients: whether blocking endothelin receptors with macitentan is associated with measurable coronary luminal dilation, considered relative to dilation after nitroglycerin. Endothelin-1 is described in the registry as a regulator of arterial health and as a possible contributor to cardiac allograft vasculopathy. This study’s registered primary measure focuses on vasomotor function rather than a comparison of clinical outcomes between treatment groups.

The study record also describes measuring blood levels of endothelin-1. However, the single registered primary outcome measure concerns the ratio of luminal dilation, and the record does not give a numerical result for that measure. It therefore does not establish from the posted results how large the ratio was, how variable it was across participants, or how precisely it was estimated.

3. Trial Design

This is a Phase 4, single-group study with no masking. The registry lists allocation as not applicable and describes one intervention arm. It is not a randomized comparison, and there is no like-for-like control arm. The study is listed as completed. The registry gives a total enrollment of 19 and reports that 16 patients had interpretable intravascular ultrasound data for the primary endpoint.

Participants in the intervention arm were scheduled to receive macitentan for one week before their routine one-year post-transplant coronary angiogram. The registry describes the dose as 10 mg orally daily, with the seventh and final dose on the day of angiography. At that visit, the study assessed coronary vasomotor function using intravascular ultrasound. The primary outcome compares luminal volume dilation after macitentan with dilation after intracoronary nitroglycerin.

The study began on 2022-05-19, and the primary completion date is 2023-02-14. These dates describe the registry timeline; they do not provide details about when individual participants were assessed or how long each participant was followed. The registry record does not report the protocol’s sample-size justification, any interim analyses, or a detailed statistical analysis plan.

Because all participants were in a single intervention arm, the endpoint is a pharmacological comparison within the study’s assessment rather than an estimate of the effect of assignment to macitentan versus assignment to a control treatment. The design can describe the measured response around the angiogram, but it cannot by itself separate that response from other influences as a randomized control comparison could. No concurrent control group is listed in the registry record.

The registry lists one primary outcome measure and no analysis entries. It identifies the endpoint summary as a median with an inter-quartile range, but the numerical summary is not reported in the registry record. Consequently, the design and intended measure can be described, while the magnitude and precision of the posted primary result cannot be assessed from this 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: Sixteen patients had interpretable IVUS data.

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 Macitentan: Nitroglycerin (NTG) Luminal Dilation Ratio as Proportion of Vasomotor Tone Attributable to Endothelin-1 (ET-1), measured over End of study week 1 (time of 1 year post-transplant coronary angiogram).

The primary endpoint is the ratio of luminal volume dilation after macitentan to luminal volume dilation after intracoronary nitroglycerin, measured using intravascular ultrasound. Nitroglycerin is described in the registry as a maximal dilator of epicardial arteries. The ratio is intended to express the relative contribution of endothelin-1 to overall resting vasomotor tone: it places dilation after endothelin receptor antagonism in relation to dilation after the comparator vasodilator.

Ratios provide a relative measure rather than simply reporting the absolute change after one intervention. In general, a ratio’s interpretation depends on how both its numerator and denominator are measured, as well as on the consistency and precision of those measurements. Here, the registry specifies the conceptual comparison but does not report the numerical ratio, its inter-quartile range, or participant-level values. The size and distribution of the endpoint therefore cannot be evaluated from the posted results.

The registry identifies the summary statistic as the median and the measure of spread as the inter-quartile range. In general, the median describes the central value in an ordered set of observations, while the inter-quartile range describes the spread of the central portion of those observations. These summaries can be useful when a distribution is skewed or when extreme values may make a mean and standard deviation less representative. The registry does not explain why this summary approach was chosen.

The endpoint was assessed at the end of study week 1, at the time of the one-year post-transplant coronary angiogram. The registry reports interpretable intravascular ultrasound data for 16 patients. It does not report a numerical endpoint result or explain how observations without interpretable imaging were handled in the endpoint analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registered design is single-group and unmasked, with allocation listed as not applicable. In general, a single-group study can characterize measurements made in participants receiving an intervention, but it does not create a randomized contrast between treatment assignments. This study’s endpoint compares two vasodilatory responses measured in the context of the angiogram; it is not a comparison of outcomes from separate randomized arms. The registry does not report further details about the order of measurements or other analytic procedures.

What does the ratio represent?

The endpoint is defined as luminal volume dilation after macitentan divided by luminal volume dilation after intracoronary nitroglycerin. In general, a ratio expresses one quantity relative to another. Its interpretation depends on both quantities, including how they were measured and whether the denominator is sufficiently informative. The registry states the intended biological interpretation: the ratio is used to express the relative contribution of endothelin-1 to resting vasomotor tone. It does not report numerical values for the ratio or the underlying dilation measurements, so the endpoint’s empirical distribution cannot be examined.

Why report a median and inter-quartile range?

The registry specifies a median and inter-quartile range for the primary outcome. In general, the median is the middle observation after values are ordered. The inter-quartile range describes the spread between the central quartiles and is less influenced by extreme observations than the range. Together, these summaries can describe the centre and spread of a distribution without requiring it to be symmetric. They do not, by themselves, quantify the precision of an estimate as a confidence interval would. The registry does not explain why these summaries were selected or report their values.

What would a confidence interval add?

In general, a confidence interval gives a range of values compatible with an estimate under a specified statistical procedure. It conveys uncertainty in the estimated quantity, whereas a descriptive spread such as an inter-quartile range describes variation among observations. A confidence interval for the primary endpoint is not reported in the registry record. No uncertainty range can therefore be used to judge how precise the estimate was.

How should the study population be understood?

The registry reports enrollment of 19 and says that 16 patients had interpretable intravascular ultrasound data. These figures describe enrollment and the availability of interpretable imaging, respectively; the registry does not provide a participant flow account or explain the status of every enrolled participant. It also does not describe an analysis population in detail, or state how missing, incomplete, or uninterpretable measurements were handled. In general, restricting an endpoint analysis to participants with interpretable measurements can affect how representative the estimate is, particularly if the availability of measurements is related to participant characteristics or outcomes. Whether that concern applies in a particular way cannot be determined from the record.

What can the design establish?

In general, random assignment can help balance measured and unmeasured factors between treatment groups, while a single-group design does not provide that same randomized control. The present study has no randomized comparison arm. Its defined endpoint contrasts the response to macitentan with the response to nitroglycerin, but this does not isolate a treatment-assignment effect against an untreated or alternative-treatment group. The registry does not report an analysis adjusting for other factors, and no such adjustment should be assumed.

What do the planning assumptions mean?

The registry describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustrations are described as targeting a stated fraction of the observed effect. These are planning assumptions, not evidence that the completed study used a two-arm design, and they are not observed power. The registry does not report the observed primary effect needed to interpret such planning illustrations, nor does it report a trial sample-size justification. In general, sample-size calculations depend on assumptions about the effect to detect, variability, statistical threshold, allocation, and analysis method; changing those assumptions changes the resulting planning estimate. No numerical planning result is reported in the registry record.

The registry lists one primary outcome measure and no analysis entries. It does not state the statistical test used, whether any covariates were considered, how uncertainty was calculated, or whether any interim analyses took place. Such details should not be inferred from the stated endpoint summary statistic. Consequently, the design and measurement definition can be explained, but the analysis that generated a primary result cannot be reconstructed from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure: the ratio of luminal dilation after macitentan to dilation after intracoronary nitroglycerin. It does not report a detailed statistical analysis plan, so it is not possible to determine whether additional outcomes or exploratory analyses were specified elsewhere, or how any multiple testing was handled. The record lists no analysis entries. There is therefore no reported set of hypothesis tests or multiplicity adjustment to interpret.

The registry identifies the primary measure’s summary as a median with an inter-quartile range, but gives neither numerical value. It also does not report a confidence interval, p-value, or other measure of inferential uncertainty for that endpoint. A reader cannot determine from the record whether the primary analysis was framed as estimation, hypothesis testing, or both. No interim analysis plan is reported in the registry record.

For the endpoint population, the registry states that 16 patients had interpretable intravascular ultrasound data. It does not report participant-level completeness, the reasons that some data were not interpretable, or a method for handling missing endpoint measurements. It also does not state whether the primary analysis included only participants with interpretable imaging or used another approach. These omissions limit assessment of the analysis population and of possible bias from unavailable measurements.

The registry reports enrollment of 19, but does not give a detailed flow from enrollment to endpoint analysis. The record therefore does not support an assumption that every enrolled participant contributed to the primary endpoint, nor does it specify an intention-to-treat approach. The relationship between the enrollment count and endpoint population is not further explained in the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry’s intervention-arm safety figures report zero serious adverse events among 19 participants at risk, zero other adverse events among 19 participants at risk, and zero deaths. No serious adverse event terms are listed. These are the counts recorded in the registry; they should be read as reported observations for this study, not as proof that the intervention carries no risk.

In general, safety counts describe events observed and recorded during the period and under the definitions used for the study. A count of zero does not establish that an event is impossible or that the risk is zero in other populations or circumstances. The registry record does not provide additional detail about safety definitions, follow-up duration for adverse-event collection, event ascertainment procedures, or confidence intervals for these counts. It also does not provide a control group for a comparative safety assessment.

The safety figures answer a different question from the primary physiological endpoint. The absence of reported serious events does not provide information about the size of the luminal dilation ratio, and it does not replace the missing numerical primary outcome. The figures should therefore be interpreted narrowly as the recorded adverse-event and death counts in the intervention arm.

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

The study evaluates a defined physiological measure in heart transplant recipients: the ratio of luminal dilation after macitentan to dilation after intracoronary nitroglycerin at the one-year post-transplant angiogram. The registry explains that this ratio is intended to represent the relative contribution of endothelin-1 to resting vasomotor tone. However, the numerical result is not reported in the registry record. There is no basis in the posted results to describe the observed ratio’s magnitude, direction, distribution, or precision.

The endpoint should not be confused with a direct measure of cardiac allograft vasculopathy progression, a clinical outcome, or a randomized treatment effect. The registry describes the study’s focus as coronary vasomotor function and lists a single intervention arm. Its comparator is intracoronary nitroglycerin within the endpoint assessment, not a separate randomized group assigned to another treatment. The design therefore does not establish what would have happened to a comparable group without macitentan.

The reported figure of 16 patients with interpretable intravascular ultrasound data identifies the population with usable imaging for the endpoint, but the record does not give their endpoint values. Enrollment was 19, and the registry does not detail the path from enrollment to interpretable measurements or how data that were not interpretable were handled. Without that information, the representativeness of the endpoint population cannot be assessed.

The registry reports no serious adverse events, other adverse events, or deaths in the intervention arm. These are safety observations, not evidence about efficacy or the underlying biological mechanism. In general, zero recorded events in a study do not establish an absence of risk, particularly without information about follow-up and event ascertainment.

Accordingly, the record supports a description of the study question, intervention, measurement, timing, and reported safety counts. It does not support a numerical conclusion about the primary endpoint, a causal claim about macitentan, or a conclusion about prevention or slowing of cardiac allograft vasculopathy. Those questions require results and analyses that are not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable for measuring a physiological response in a specialized clinical setting and defining that response as a ratio between dilation after macitentan and dilation after intracoronary nitroglycerin. The ratio is intended to express a biological contribution to resting vasomotor tone, rather than to compare clinical event rates between treatment groups. Understanding that distinction is important when interpreting what an endpoint can establish.

The single-group, unmasked design is also central to interpretation. It can describe measurements made during the study assessment, but it does not offer a randomized control arm for estimating the effect of treatment assignment. The comparator embedded in the endpoint is a pharmacological reference measurement, not an independent group. This distinction prevents the physiological comparison from being misread as a randomized efficacy comparison.

There is an important gap between the outcome’s detailed definition and the results available in the registry. The record specifies the median and inter-quartile range as the summary approach and identifies 16 patients with interpretable imaging, but does not report the numerical summary. Without the estimate and its variability, the central statistical questions—what response was observed and how precisely it was measured—cannot be answered.

The record also illustrates why analysis-population information matters. Enrollment is reported, as is the number with interpretable imaging, but the handling of unavailable endpoint data is not described. In general, clear reporting of participant flow and missing-data methods helps readers judge whether an analyzed population could differ meaningfully from the enrolled population. The registry record does not provide those details.

Finally, a planning illustration based on an observed effect should not be confused with an observed study result or with the study’s original design justification. The registry describes assumptions for such illustrations, but does not report the endpoint estimate needed to interpret them. Separating planning calculations, outcome estimation, and causal comparison is essential for a statistically sound reading of this study.

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 main limitation for interpreting the registered primary endpoint is that its numerical result is not reported in the registry record. Although the endpoint definition and intended summary statistic are stated, the median and inter-quartile range are absent. No confidence interval or other measure of precision is reported, so neither the size nor uncertainty of the primary estimate can be evaluated.

The study has one intervention arm, no masking, and no randomized control group. The endpoint’s comparison with intracoronary nitroglycerin is part of the physiological measurement, not a between-group treatment comparison. As a result, the design does not provide a randomized estimate of the effect of macitentan relative to a control treatment.

The registry reports that 16 patients had interpretable intravascular ultrasound data, but does not describe participant flow or explain why measurements were not interpretable for others. It does not state how unavailable endpoint data were handled or identify the analysis population in further detail. The effect of missing or uninterpretable measurements on the estimate therefore cannot be assessed.

The statistical analysis plan is not reported in the registry record. Details about hypothesis tests, adjustment for other variables, confidence-interval methods, and interim analyses are not available. The registry also does not report a sample-size justification. Planning assumptions described for illustrations do not replace these study-specific methods.

For safety, the registry reports zero recorded adverse events and deaths, but does not provide further information about event definitions, ascertainment, or follow-up duration. The absence of a control group also limits comparative interpretation of these counts. These limitations constrain what can be concluded from the registry record even though the study status is listed as completed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Endothelin-1 and Cardiac Allograft Vasculopathy (CAV) — NCT05373108.
• Registry record last updated 2024-03-12; status last verified 2024-02.
• Results first posted 2024-03-12.
• 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.

18. Record Summary

NCT05373108, “Endothelin-1 and Cardiac Allograft Vasculopathy (CAV),” is a completed Phase 4, single-group, unmasked study sponsored by the University of California, Los Angeles. It enrolled 19 participants and evaluated a one-week course of macitentan before the routine one-year post-transplant coronary angiogram. The primary measure was the ratio of luminal dilation after macitentan to dilation after intracoronary nitroglycerin, assessed by intravascular ultrasound. The registry reports interpretable imaging for 16 patients but does not report the primary endpoint’s numerical summary. It records zero serious adverse events, zero other adverse events, and zero deaths in the intervention arm. The registry record does not report a detailed statistical analysis plan or handling of unavailable endpoint data.