Inhaled Nitric Oxide for Pulmonary Hypertension and Bronchopulmonary Dysplasia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Nitric Oxide for Pulmonary Hypertension and Bronchopulmonary Dysplasia (NCT03576885), a randomized phase 1, phase 2 study. The primary outcome is Death.

2. Clinical Question

3. Trial Design

NCT03576885, titled “Inhaled Nitric Oxide for Pulmonary Hypertension and Bronchopulmonary Dysplasia,” is recorded as a phase 1 and phase 2 trial. Its official title is “Treatment of Delayed Pulmonary Transition in Extremely Preterm Infants & Bronchopulmonary Dysplasia.” AdventHealth is listed as the sponsor. The study began on 2019-07-15, had a primary completion date of 2023-10-09, and is recorded as terminated.

The registry describes a randomized, quadruple-masked, parallel-group design. Enrollment was 32. For the posted primary outcome, the active and placebo groups each include 16 participants. The listed interventions are inhaled nitric oxide and placebo. Both treatment descriptions specify a starting level of 20 ppm and continuation for 2 weeks or until resolution of pulmonary hypertension, whichever came first.

The record also describes enrolled infants without evidence of pulmonary hypertension as a control group for incidence of death or bronchopulmonary dysplasia. However, the posted results for the primary outcome list only the active and placebo treatment groups. Results for the separately described control group are not reported in the registry record. The relationship between that group and the randomized comparison is not further detailed in the registry record.

The design description identifies the trial as randomized and masked, but the method used to generate the allocation sequence, conceal allocation, and maintain masking is not reported in the registry record. The sample-size justification and the intended enrollment target are also not reported in the registry record. No reason for termination is reported in the registry record, so the status alone does not establish why the trial ended.

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.

6. Primary Endpoint

The registry lists the primary outcome as Death, measured over 36 weeks post menstrual age.

The posted primary endpoint is the incidence of death, measured as the count of participants who died by 36 weeks post menstrual age. The registry identifies the outcome unit as participants and describes the measure as “Incidence of death.” Each randomized treatment group has 16 participants and one recorded death.

Death is a clinically important outcome and is directly countable. In a trial focused on extremely preterm infants, the stated study rationale also discusses a combined outcome of death or bronchopulmonary dysplasia. However, the posted primary outcome is death alone, rather than the combined outcome. A separate bronchopulmonary dysplasia result is not reported in the registry record, and the posted primary endpoint does not show whether participants who survived developed bronchopulmonary dysplasia.

The trial description names oxygenation and pulmonary artery pressure as additional aims. Those outcomes could describe aspects of physiological response, while death records whether the event occurred during the stated follow-up period. They are distinct questions and should not be treated as interchangeable with the primary endpoint. The registry record gives 36 weeks post menstrual age as the timeframe for death; further details about outcome ascertainment and analysis are not reported in the registry record.

7. Results Posted in the Registry

• Treatment Group - Active: 6.2% (1/16) versus 6.2% (1/16) on control; risk difference 0.0 percentage points (95% CI -16.8 to 16.8), risk ratio 1.00 (0.07–14.64); unadjusted two-proportion z-test p = 1.000.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Pulmonary Hypertension

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Treatment Group - Active: 68.8% (11/16) versus 93.8% (15/16) on control; risk difference -25.0 percentage points (95% CI -50.6 to 0.6), risk ratio 0.73 (0.51–1.04); unadjusted two-proportion z-test p = 0.070.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment Group - Active and the control. The interval gives the range of effects that remain compatible with the data.

The registry posts pulmonary hypertension as a secondary outcome and lists one secondary outcome measure. This outcome is related to the trial’s stated focus on early pulmonary hypertension, while the primary posted endpoint is death. The outcomes address different aspects of the study question: a secondary pulmonary hypertension measure cannot substitute for the death result, and the death result does not settle the pulmonary hypertension question.

At a broad level, the posted secondary comparison points toward fewer participants with pulmonary hypertension in the active group than in the placebo group, but its unadjusted statistical result does not provide strong evidence against no difference under conventional interpretation. Its confidence interval spans zero. The point estimate should therefore be read alongside its uncertainty, not as a conclusive treatment effect. The registry’s stated aims also mention pulmonary artery pressure and oxygenation, but results for those measures are not reported in the registry record.

Secondary outcomes usually carry less weight than a prespecified primary outcome because they may be numerous, exploratory, or interpreted without the same priority in the analysis plan. Testing multiple outcomes can increase the chance of obtaining an apparently notable result by chance if no adjustment or hierarchy is used. Whether a formal multiplicity strategy was planned for this trial is not reported in the registry record. The secondary p-value is explicitly unadjusted, so it should not be treated as if it accounts for testing other outcomes.

The secondary findings add context to the trial’s clinical question, but they do not overturn or resolve the primary result. They are best viewed as uncertain evidence that may motivate further study, rather than as a stand-alone conclusion. The registry record does not report additional secondary analyses that would clarify consistency across measures or time points.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Pulmonary Hypertension

9. Statistical Interpretation

10. Statistical Methods Explained

The registry posts counts for a binary outcome: each participant either had the event or did not. For death, it reports one event in each treatment group. For pulmonary hypertension, it reports the number of participants with the event in each group. The comparison summaries express group differences using risk differences, with accompanying confidence intervals and unadjusted p-values.

What does a risk difference describe?

In general, a risk difference compares the proportion with an event in one group with the proportion in another. A value of 0 indicates equal observed proportions; a negative value in the active-versus-placebo comparison indicates a lower observed proportion in the active group. This is a descriptive contrast of the trial groups, not by itself proof that treatment caused a difference. Randomization supports a comparison between assigned groups, but interpretation still depends on the conduct of the trial, completeness of follow-up, and the analysis used.

What does the p-value tell the reader?

In general, a p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of the statistical test. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. The registry labels the posted p-values as unadjusted. The p-value for death is 1.0; the secondary pulmonary hypertension comparison has an unadjusted p-value of 0.07. The registry record does not report the test method or a multiplicity adjustment.

How should the confidence interval be read?

In general, a confidence interval describes the uncertainty around an estimated effect under a statistical procedure. A wide interval indicates that the data are compatible with a broad range of possible effects. An interval spanning zero for a risk difference includes the possibility of no difference as well as effects in either direction. It should not be read as a range in which the true value is guaranteed to fall. The intervals posted for both outcomes span zero, and their width matters when interpreting the point estimates.

The registry also lists relative risk and odds ratio summaries for the comparisons. In general, these are alternative ways of expressing contrasts between event occurrence in two groups. Their interpretation can be difficult when the number of events is small, and their intervals may be imprecise. The posted relative risk and odds ratio estimates for death have broad intervals. The record does not report adjusted estimates or additional analyses that could change how the primary result is interpreted.

What do the planning illustrations mean?

The record includes a planning illustration based on the observed pulmonary hypertension effect, not the trial’s own design. It uses a two-sided significance level of 0.05, equal allocation, and a normal approximation. The illustration gives participants per arm for 80% and 90% power when planning for 100%, 75%, or 50% of the observed effect. For 100% of the observed effect, the figures are 38 participants per arm for 80% power and 50 participants per arm for 90% power. For 75% of the observed effect, they are 58 and 77 participants per arm, respectively. For 50% of the observed effect, they are 109 and 146 participants per arm, respectively.

These figures are planning illustrations, not observed power and not evidence that the trial was designed to enroll those numbers. Because they use the observed effect as their starting point, they depend on an estimate from the trial itself; smaller assumed effects require larger illustrative sample sizes. The trial’s own sample-size assumptions and justification are not reported in the registry record.

In general, over-dispersion is a concern when observed variability is greater than a model expects, because standard errors and confidence intervals may then be too small if the extra variability is ignored. The posted endpoints are participant counts for binary outcomes, and no over-dispersion assessment or model-based variance adjustment is reported in the registry record. The record also does not report whether the primary analysis was adjusted for other variables. The posted results therefore support a straightforward description of the reported group counts and unadjusted comparisons, while leaving the fuller analysis plan unspecified.

11. Confidence Intervals and Precision

The death estimate is a risk difference of 0.0, with a confidence interval from -0.168 to 0.168. The interval includes zero, consistent with no observed difference, but it also extends in both directions. Its width shows that the primary result is imprecise: the point estimate alone does not rule out differences that could matter, and the data do not identify the direction of any underlying difference with confidence.

In general, a confidence interval reflects both the observed estimate and the amount of information available. When event counts and group sizes are limited, estimates can be uncertain even when the point estimate is exactly zero. The posted death counts are one in each group, with 16 participants per group. The interval should therefore be considered alongside the point estimate, rather than treating the point estimate as a complete description of the evidence.

The pulmonary hypertension risk-difference interval runs from -0.506 to 0.006. It also spans zero and allows a range of possible group differences. This is relevant context for reading the secondary comparison, but it does not change the primary endpoint’s interpretation.

In general, a confidence interval is not a guarantee that the true effect lies within its endpoints, nor does an interval spanning zero prove that there is no effect. It describes uncertainty under the method used to construct it. The registry does not report the interval method or adjusted analyses. The available precision is therefore best described through the posted estimates and intervals, without assigning more certainty than they support.

12. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan, a prespecified hierarchy of outcomes, or a method for adjusting tests across multiple outcomes. It lists a primary death outcome and one secondary pulmonary hypertension outcome, while the trial description also discusses bronchopulmonary dysplasia, oxygenation, and pulmonary artery pressure. Results for some of these stated aims are not reported in the registry record. Without a reported analysis plan, it is not possible to determine how the outcomes were prioritized or whether additional comparisons were planned.

The posted p-values are unadjusted. In general, when several outcomes or comparisons are tested, interpreting each p-value in isolation can overstate the strength of evidence because the chance of at least one apparently unusual result can increase. An adjustment or prespecified testing hierarchy can address this issue, but neither is described in the registry record. The secondary result should consequently be treated as less definitive than a result from a clearly specified, multiplicity-controlled analysis.

Missing-data methods and analysis populations are not reported in the registry record. The record does not say whether all randomized participants were included in the primary analysis, how withdrawals or unavailable outcome data were handled, or whether any participants were excluded after randomization. The posted group sizes and outcome counts do not by themselves establish that follow-up was complete.

Interim analyses, stopping rules, and the reason the study was terminated are also not reported in the registry record. These details matter for understanding how the observed results were reached, but their absence does not establish that a particular procedure was or was not used. The registry reports no analysis results beyond the posted comparisons. These reporting gaps limit assessment of the full statistical conduct and should be kept separate from the numerical results that are available.

13. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: nec (18.8%), ivh (12.5%).

The registry reports serious adverse events affecting 2 participants in the active group and 5 in the placebo group. It reports other adverse events affecting 14 participants in each group. Deaths are listed as 1 in each group. The most frequently listed serious adverse event terms are NEC, 18.8%, and IVH, 12.5%.

These figures describe the posted safety record; they are not the primary efficacy comparison. Counts of participants with events do not necessarily describe how many total events occurred, their timing, severity beyond the registry classification, or whether events were judged related to treatment. The registry record does not provide further details on those points. It also does not explain the relationship between the listed deaths and the adverse-event categories.

In general, safety counts from a trial with limited enrollment can be unstable and should be interpreted with attention to the number of participants at risk and the way events were collected. The record lists 16 participants at risk in each group. The event figures alone do not establish a causal explanation or a comparative safety conclusion.

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

The primary result describes the death outcome recorded for the active and placebo groups by 36 weeks post menstrual age. One participant in each group died, and the estimated risk difference is 0.0. The confidence interval is broad and spans zero, so the estimate is compatible with a range of group differences. The result is not evidence that the treatments are equivalent, and it does not establish the absence of a difference.

The result also does not answer every question named in the trial description. The study rationale and objectives include death or bronchopulmonary dysplasia, pulmonary artery pressure, and oxygenation. The posted primary endpoint measures death alone. Separate results for bronchopulmonary dysplasia, pulmonary artery pressure, and oxygenation are not reported in the registry record. A conclusion about those outcomes cannot be drawn from the death comparison.

The secondary pulmonary hypertension data offer a separate, uncertain comparison and should not be substituted for the primary result. The secondary p-value is unadjusted, and the registry does not describe a multiplicity plan. These features call for cautious interpretation rather than a definitive claim about treatment effect.

The trial is recorded as terminated, with enrollment of 32. The registry does not report why it was terminated, whether all planned follow-up was completed, or the study’s sample-size justification. Those omissions limit understanding of the conduct and intended precision, but they do not change the observed counts. The most defensible reading is confined to the posted outcomes, their estimated differences, and their uncertainty.

These results concern the participants and comparisons recorded in this trial. They do not establish what would happen in other populations, under different treatment conditions, or for outcomes that were not reported. No medical decision should be based on this statistical summary alone.

15. Why This Trial Matters Statistically

This trial raises an important statistical distinction between a plausible clinical rationale and evidence from a measured endpoint. Its stated hypothesis concerns early pulmonary hypertension in extremely preterm infants and includes death or bronchopulmonary dysplasia, oxygenation, and pulmonary artery pressure. The primary result posted is death alone. Keeping the endpoint definition in view prevents readers from extending a finding about one outcome to outcomes that were not reported.

The equal death counts produce a risk-difference estimate of 0.0, but the confidence interval makes clear that the estimate is not precise. This is a useful example of why a point estimate and its uncertainty need to be interpreted together. A result that does not show a difference in the observed counts is not the same as evidence that clinically relevant differences have been excluded.

The registry also illustrates how secondary findings should be handled. The pulmonary hypertension comparison aligns with the study’s focus, but it is secondary, unadjusted, and uncertain. Without a reported analysis plan or multiplicity approach, a reader should not elevate one secondary result to a definitive conclusion.

Finally, the planning illustrations are distinct from the trial’s actual design. They use the observed effect and are not observed power or evidence of the intended sample size. The trial’s justification and reason for termination are not reported in the registry record. Recognizing these limits helps separate the numerical information available from explanations the record does not establish.

16. 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 posted primary results include one death in each of the two treatment groups, with 16 participants per group. This limited amount of outcome information is reflected in the wide confidence interval around the risk difference. The estimate is therefore not precise enough to rule out a range of possible differences.

The primary endpoint is death, while the stated study hypothesis includes death or bronchopulmonary dysplasia. A separate bronchopulmonary dysplasia result is not reported in the registry record. Pulmonary artery pressure and oxygenation are also named in the trial objectives, but results for those measures are not reported. The available outcome record consequently covers only part of the stated research question.

The registry describes a control group of enrolled infants without evidence of pulmonary hypertension, but the posted primary results list active and placebo groups only. Results for the separately described control group are not reported in the registry record, and the relationship of that group to the randomized comparison is not explained. This limits interpretation of the full design.

The record lists the study as terminated but does not report the reason, the sample-size justification, or whether the intended enrollment was achieved. It does not report methods for missing data, analysis populations, interim analyses, or the statistical analysis plan. The allocation and masking procedures are also not described beyond the design labels. These gaps limit assessment of study conduct and analysis, without establishing that any particular procedure was absent.

Finally, the secondary comparison is unadjusted and its interval includes zero. The registry does not report a multiplicity strategy. The secondary result should therefore be considered exploratory in interpretation, while the primary result remains limited by imprecision and the scope of the endpoint actually posted.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Inhaled Nitric Oxide for Pulmonary Hypertension and Bronchopulmonary Dysplasia — NCT03576885.
• Registry record last updated 2025-01-15; status last verified 2025-01.
• Results first posted 2025-01-15.
• 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.

20. Record Summary

NCT03576885 is recorded as a randomized, quadruple-masked, parallel phase 1 and phase 2 trial sponsored by AdventHealth. It enrolled 32 participants and is listed as terminated. The primary outcome is incidence of death by 36 weeks post menstrual age, with one recorded death in each 16-participant group. The risk difference is 0.0, with a confidence interval from -0.168 to 0.168 and an unadjusted p-value of 1.0.

Pulmonary hypertension is listed as a secondary outcome. Its comparison is unadjusted, and the registry includes planning illustrations based on the observed effect; those illustrations are not the trial’s own design or observed power. Results for bronchopulmonary dysplasia, oxygenation, and pulmonary artery pressure are not reported in the registry record. The reason for termination, sample-size justification, missing-data methods, analysis populations, and multiplicity strategy are also not reported.