The Effects of Inhaled Nitric Oxide After Fontan Operation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Effects of Inhaled Nitric Oxide After Fontan Operation (NCT00945529), a non-randomized phase 2, phase 3 study. The primary outcome is Length of Hospital Stay Following Fontan.

2. Clinical Question

The study rationale focused on postoperative fluid balance and pleural effusions. Its stated hypothesis was that inhaled nitric oxide would improve fluid balance, decrease the incidence of pleural effusions, and shorten hospital stay. These are hypotheses, not findings: the registry record gives no numerical result for the primary endpoint or the secondary outcome.

The primary endpoint was length of hospital stay until discharge, measured in days. The named secondary outcome was the percent of patients with significant pleural fluid collections requiring thoracostomy drainage. The record does not report the values for either outcome, so it is not possible to describe the observed difference, its direction, or its precision.

3. Trial Design

The registry identifies this as a completed Phase 2 and Phase 3 study, with a start date of 2008-02 and primary completion in 2011-12. Enrollment is listed as 21. The prospective intervention group is described as receiving inhaled nitric oxide; the control group is a historical group that did not receive it. The record lists 23 patients in that historical group and 21 in the intervention group for adverse-event reporting.

The design fields describe allocation as non-randomized, masking as none, and the model as single group. The record also describes a historical control group, so the comparison is not a randomized, concurrent two-arm comparison. The registry notes that the arms are not a like-for-like control comparison. These design details matter because the groups may differ for reasons other than treatment, and the record does not establish that differences between them were controlled in an analysis.

The intervention was inhaled nitric oxide after Fontan operation, described in the study summary as lasting 54 hours. The primary outcome was length of hospital stay until discharge. A secondary outcome concerned significant pleural fluid collections requiring thoracostomy drainage. The record lists two outcome measures but reports no analyses.

Some design details that would help assess the comparison are not reported in the registry record, including eligibility criteria, how the historical controls were selected, and whether the groups were comparable at baseline. The record also does not report a statistical analysis plan, the timing of any outcome assessments beyond the primary endpoint timeframe, or how departures from the intended intervention were handled. The available design description therefore supports a cautious account of the comparison, but not a reconstruction of the full protocol.

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

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: Prospective intervention group - consent obtained prior to research activity Historical control group - data collection only - waiver of consent

6. Primary Endpoint

The registry lists the primary outcome as Length of Hospital Stay Following Fontan, measured over until hospital discharge.

The primary endpoint is length of hospital stay following Fontan operation, measured in days until hospital discharge. The registry specifies that the outcome is a mean with full range as its dispersion summary. It does not provide the mean, the range, or a comparison between groups, so the recorded endpoint description alone cannot show how long participants stayed or whether the groups differed.

Length of stay is a patient-level measure of time spent in hospital and can reflect multiple aspects of postoperative recovery and care. In this study, it was relevant to the stated interest in postoperative morbidity and the possibility of shortening hospitalization. It is not a specific measure of fluid balance or pleural effusion, however; the study separately names pleural fluid collections requiring thoracostomy drainage as a secondary outcome.

In general, a mean describes the arithmetic average, while a full range describes the minimum and maximum observed values. Length-of-stay data can be unevenly distributed, and a small number of longer stays can influence the mean. The range gives information about the spread of observations but does not, by itself, describe how values are distributed between the endpoints. These are general interpretive points, not claims about the unreported study data.

Because the registry record contains no endpoint results or analysis, neither the magnitude nor the precision of a treatment-group contrast can be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies length of hospital stay as the primary endpoint and describes its summary as a mean with full range. It does not report the numerical summaries, an inferential analysis, or a confidence interval. The method used to compare the prospective group with historical controls is not reported in the registry record. It would therefore be inappropriate to attribute a particular statistical test, adjustment method, or model to the study.

What a mean and range describe

In general, the mean is the arithmetic average of the observed values. The full range gives the smallest and largest values. Together, they provide a basic description, but the range does not show how frequently values occur across the interval. A mean may also be influenced by a small number of unusually long stays. These are general properties of the summaries named in the registry, not interpretations of study-specific values, which are not reported.

Why comparison design matters

In a randomized trial, random assignment is intended to balance measured and unmeasured characteristics between groups on average. This study is listed as non-randomized, with a historical control group and no masking. The groups were therefore not assigned concurrently by random allocation. In general, observed differences in outcomes in a historical comparison may reflect the intervention, differences between the populations, changes over time, or other factors. Statistical adjustment can sometimes address measured differences, but it cannot automatically remove unmeasured confounding. The registry does not report whether adjustment was undertaken or which covariates might have been used.

The record describes the model as single group while also listing a historical control group. This makes it especially important not to assume that the study used a conventional randomized two-arm analysis. The meaning of that model designation is not further explained in the registry record.

Precision and uncertainty

In general, a confidence interval gives a range of values compatible with the data under a specified statistical model and reflects uncertainty in an estimate. A narrow interval indicates greater precision than a wide interval, all else being equal. No confidence interval or endpoint estimate is reported for length of stay, so the precision of a treatment contrast cannot be assessed. A p-value, if reported, would address compatibility with a null hypothesis under a model; it would not by itself describe the size or practical importance of an effect. No p-value is reported in the registry record.

For count or rate outcomes, over-dispersion means that variability is greater than a statistical model assumes. In general, failing to account for over-dispersion can make uncertainty estimates too small. This is a general statistical consideration, not a statement that over-dispersion was present or that a count model was used in this trial. The registry does not report an analysis of the pleural-fluid outcome.

Planning illustrations are not trial results

The sample-size illustrations are described as planning calculations based on the observed effect, not as the study's own design justification. Their assumptions are a two-sided significance level of 0.05, equal allocation between groups, a normal approximation, and detection of the stated fraction of the observed effect. Such calculations ask how many participants per arm would be needed under chosen assumptions. They are not observed power, do not establish that the study had that power, and do not show that an effect was present. The registry does not report the trial's sample-size justification, so the illustrations should not be treated as a record of the original planning process.

The record does not report an analysis plan, the handling of missing outcomes, or an analysis population. It also does not identify whether the primary endpoint was analyzed using an unadjusted or adjusted comparison. Without those details and the underlying endpoint results, the statistical approach cannot be independently evaluated from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: length of hospital stay as the primary endpoint, and the percent of patients with significant pleural fluid collections requiring thoracostomy drainage as a secondary outcome. It reports zero analyses. No multiplicity strategy, such as a hierarchy for testing outcomes or an adjustment for multiple comparisons, is reported in the registry record. It is therefore not possible to determine whether any statistical testing was planned or how multiple outcome questions would have been handled.

Missing-data methods and the amount of missing outcome data are not reported in the registry record. The record does not state whether all enrolled participants contributed to the primary endpoint, how participants without an observed discharge measure were handled, or whether any sensitivity analyses were performed.

The analysis population is also not reported. The record does not specify whether the intended analysis was based on all enrolled participants, those who received the intervention as intended, or another defined group. The enrollment field lists 21, while adverse-event reporting lists 21 participants in the intervention group and 23 in the historical control group; the registry does not explain the relationship between those counts. They should not be treated as interchangeable descriptions of one analysis population.

These omissions limit interpretation of both statistical significance and generalizability. They do not demonstrate that missing data, multiple testing, or population exclusions affected the results; they mean that the registry record does not provide enough information to evaluate those issues.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: prolonged hospital stay due to infection (21.7%), prolonged hospital stay due to pleural effusion (17.4%), prolonged hospital stay due to feeding issue (4.8%), prolonged hospital stay due to atelectasis (4.8%), reoperation (4.8%).

The registry reports serious and other adverse-event figures separately for the historical control group and the intervention group. For the historical control group, the serious-event figures list 23 at risk and 8 affected; the other-event figures list 23 at risk and 7 affected. For the intervention group, the serious-event figures list 21 at risk and 5 affected; the other-event figures list 21 at risk and 6 affected. These are the reported counts, not a statistical comparison between groups.

The registry also lists serious-event terms with percentages: prolonged hospital stay due to infection, 21.7%; prolonged hospital stay due to pleural effusion, 17.4%; prolonged hospital stay due to feeding issue, 4.8%; prolonged hospital stay due to atelectasis, 4.8%; reoperation, 4.8%; and prolonged hospital stay due to sepsis, 4.8%. The record does not give further detail about how these term-specific percentages were calculated, so they should be read as recorded rather than used to infer additional counts.

Deaths are not reported in the registry record. The figures do not establish that the groups had comparable safety follow-up or that any difference was caused by treatment. No formal statistical safety comparison is reported.

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

The record establishes that a prospective group received inhaled nitric oxide after Fontan operation and that a historical group did not. It identifies length of hospital stay as the primary endpoint and pleural fluid collections requiring thoracostomy drainage as a secondary outcome. It also records adverse-event counts and selected serious-event terms. These details describe the study question and the reported safety information.

The record does not establish whether inhaled nitric oxide shortened hospital stay, changed fluid balance, or affected pleural effusions. Numerical results for the primary and secondary outcomes are not reported, and the registry lists no analyses. There is no effect estimate, confidence interval, or statistical test result from which to assess the size or precision of a group difference. The study's stated hypothesis should not be read as an outcome finding.

Even if a numerical contrast were available, a non-randomized comparison with historical controls would require caution. In general, differences between groups may have explanations other than the intervention. The registry record cautions that the arms are not a like-for-like control comparison, and it does not describe an adjustment strategy that would resolve this concern.

The adverse-event figures provide descriptive counts but do not answer the primary efficacy question, and they do not supply a formal safety comparison. The absence of reported death counts or outcome analyses should not be interpreted as evidence that no such events or analyses existed; it means they are not reported in the registry record.

The appropriate reading is therefore limited: the record documents a completed study design and selected safety data, but it does not provide the outcome results needed to quantify or interpret the treatment comparison. No claim that the intervention did or did not change clinical outcomes is supported by the results recorded.

13. Why This Trial Matters Statistically

This trial raises statistical issues that are common in clinical research: how to interpret a historical control, how to distinguish a study hypothesis from a result, and how to assess uncertainty when outcome estimates are missing. Its registry record makes the design distinction explicit by identifying non-randomized allocation and noting that the arms are not a like-for-like control comparison. That warning is important because a group difference in a historical comparison cannot automatically be attributed to the intervention.

The primary endpoint is a clinically interpretable measure, length of hospital stay, summarized as a mean and full range. But the registry reports no numerical endpoint results and no analyses. This shows why an endpoint definition and a stated hypothesis are not substitutes for an estimated effect with information about its precision. Without those results, neither the magnitude nor direction of a group contrast can be assessed.

The record also demonstrates why safety counts must be kept distinct from efficacy analyses. Serious and other adverse-event counts are available, while the primary outcome and the listed pleural-fluid outcome have no reported numerical results. Those kinds of evidence answer different questions and should not be combined into a single conclusion about treatment effect.

Finally, planning illustrations are not trial results or evidence of observed power. Their assumptions may help readers understand hypothetical sample-size requirements, but they do not reconstruct the study's original design justification, which is not reported in the registry record. The central statistical lesson is to separate what the study set out to examine, what its design can support, and what its posted results actually quantify.

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 interpretation is that the registry record does not report numerical results for the primary endpoint or the named secondary outcome. It also reports zero analyses. Consequently, the clinical comparison cannot be quantified, and its statistical precision cannot be assessed.

The comparison is non-randomized and uses historical controls, rather than a concurrent randomized control group. This leaves the possibility that group differences reflect factors other than inhaled nitric oxide. The registry explicitly cautions that the arms are not a like-for-like control comparison. It does not report how historical controls were selected, baseline characteristics, or any adjustment for differences between groups.

The record lists no masking and describes the model as single group, while also identifying historical controls. It does not further explain the relationship between that model label and the control group. The enrollment field lists 21, whereas adverse-event reporting lists 23 historical controls and 21 intervention participants; how these counts relate to outcome analyses is not reported.

Further limitations include the absence of reported information about missing outcome data, the analysis population, multiplicity handling, and the statistical analysis plan. The registry gives the primary endpoint timeframe as until hospital discharge, but does not report the endpoint values. Death counts are not reported. These gaps limit assessment of both efficacy and safety and should not be filled by assumptions about the protocol or analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: The Effects of Inhaled Nitric Oxide After Fontan Operation — NCT00945529.
• Registry record last updated 2023-05-19; status last verified 2023-04.
• Results first posted 2023-05-19.
• 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

The completed study examined inhaled nitric oxide after Fontan operation, described as being given for 54 hours. The registry lists Phase 2 and Phase 3, non-randomized allocation, no masking, a single-group model, and enrollment of 21. A prospective intervention group was compared with a historical control group that did not receive inhaled nitric oxide; the record cautions that these are not like-for-like groups.

The primary endpoint was mean length of hospital stay in days until discharge, with full range specified as the dispersion summary. A secondary outcome concerned significant pleural fluid collections requiring thoracostomy drainage. Numerical outcome results and analyses are not reported in the registry record. Serious and other adverse-event counts are listed for both groups, as are selected serious-event terms and percentages; deaths are not reported.

The record does not report the statistical analysis plan, missing-data methods, analysis population, or multiplicity approach. Accordingly, it documents the study question and design, but does not support a numerical interpretation of the treatment comparison.