Inhaled Nitric Oxide (iNO) as an Adjunct to Neonatal Resuscitation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Nitric Oxide (iNO) as an Adjunct to Neonatal Resuscitation (NCT01220687), a randomized na study. The primary outcome is Maximum Factional Inspired Oxygen Percent (FiO2).

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel-group pilot trial sponsored by the University of Oklahoma. The registry lists the phase as not applicable and the study status as completed. Enrollment was 33. The registry records a start in 2011-04 and primary completion in 2017-01.

The two groups received either inhaled nitric oxide or nitrogen, each described at 20 ppm at the beginning of the study and with a gradual taper beginning at 10 minutes. Both were described as completely discontinued by 17 minutes. The study summary frames the intervention as nitric oxide alongside oxygen in the first 20 minutes of life for infants needing breathing support. The stated primary outcome timeframe is 20 minutes.

Randomization means assignment to the groups was intended to occur by chance, while quadruple masking indicates that the record classifies the trial as masked at four levels. The identities of the masked groups or the practical masking procedures are not reported in the registry record. A parallel design means the groups are compared over the same study period rather than participants crossing between treatments; details of follow-up and allocation procedures are not reported in the registry record.

The posted primary outcome has 14 participants in each group. The registry does not explain how these outcome counts relate to total enrollment, and no analysis population is specified. The trial is identified as a pilot, but the sample-size justification, recruitment targets, and any protocol-defined precision goals are not reported in the registry record. The design information therefore supports a description of the randomized comparison, but not a reconstruction of all operational or planning choices.

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.

Before assignment: 64 consented mothers or infants met subsequent exclusion criteria. Of those, only 33 were enrolled at time of delivery. Most common exclusion was aging out of gestational age limit, precipitous delivery, or no team available.

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 Maximum Factional Inspired Oxygen Percent (FiO2), measured over 20 minutes.

The primary endpoint is maximum fractional inspired oxygen (FiO2), reported as a mean, with a timeframe of 20 minutes. FiO2 describes the oxygen concentration in the gas mixture being delivered to an infant. In this trial, the maximum value over the stated period is used to represent the highest supplemental oxygen exposure recorded during resuscitation.

The registry’s stated purpose is to investigate whether iNO decreases supplemental oxygen exposure in preterm infants requiring CPAP or PPV during resuscitation. A maximum captures the peak level reached, rather than the duration spent at each oxygen level or total oxygen exposure over time. Those are distinct ways of characterizing exposure, and the posted primary endpoint is not itself a measure of either later lung health or other clinical outcomes.

The registry lists the endpoint dispersion as an interquartile range, but does not post a spread value for either group. It reports group values of 48.0 for placebo and 39.0 for iNO, with additional endpoint bounds of 34.73 to 68.2 and 20.98 to 53.26, respectively. The record does not identify those bounds as a particular type of interval in the endpoint display, so they should not be assigned a confidence-interval interpretation without further documentation. The endpoint is relevant to the stated oxygen-exposure question, while its clinical meaning depends on how it relates to outcomes beyond the short resuscitation period.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary analysis reported by the registry is a two-sided t-test comparing final mean values between the randomized groups. A t-test evaluates whether the observed difference in group means is inconsistent with a null hypothesis of no mean difference, subject to the test’s assumptions. A two-sided test allows evidence of a difference in either direction. The posted p-value is 0.001, and the reported mean difference is 9. The record does not state whether the test was adjusted for any baseline variables or other factors.

What does the reported p-value tell us?

In general, a p-value measures how unusual the observed test statistic, or a more extreme one, would be if the null hypothesis and the statistical model assumptions were true. It is not a measure of the probability that the result happened by chance, and it is not the probability that the treatment has no effect. A small p-value can indicate statistical evidence against the null model, but it does not convey the estimated effect’s clinical importance or precision. Those require the estimate, an interval where available, and context about the outcome.

The registry does not report a confidence interval for the primary mean difference. In general, a confidence interval expresses the uncertainty around an estimate under a specified method: narrower intervals indicate greater precision, while wider intervals indicate less. Because there is no posted interval for the primary contrast, the uncertainty around the reported mean difference cannot be described using one. The endpoint’s listed bounds should not be treated as the contrast interval; the record does not label them that way.

How should the endpoint summaries be read?

The primary outcome is described as a mean with interquartile-range dispersion. A mean is a summary of the average observed values, while an interquartile range describes the central spread of observations. The registry gives group values but no spread values, so the stated dispersion cannot be used to assess the distribution or variability within each arm. The values labeled as bounds are posted for each group, but the registry does not identify their statistical interpretation in the endpoint record. The sponsor’s reported test is a t-test; details of diagnostic checks or alternative methods are not reported in the registry record.

In general, a t-test’s interpretation relies on assumptions about the sampling distribution of the mean and the observations being analyzed. With small groups, individual observations can have substantial influence, and departures from assumptions may matter. The registry does not report distributional diagnostics or a justification for the method. This does not demonstrate that the method was inappropriate; it means the record does not provide enough detail to evaluate those aspects of the analysis.

What is the role of the secondary comparisons?

For posted binary outcomes, recalculated risk differences compare the observed proportions between groups using the posted counts and denominators. A risk difference is expressed as the proportion in the iNO group minus the proportion in the placebo group in the recalculation. Negative estimates indicate fewer observed participants with the outcome in the iNO group; positive estimates indicate more. These are simple, unadjusted comparisons and are not substitutes for the sponsor’s own analysis. The registry has no sponsor-reported analyses for these listed secondary comparisons.

For the posted comparisons, the recalculated intervals span values on both sides of no difference. In general, an interval that includes no difference means the data do not precisely distinguish a difference in one direction from no difference or a difference in the other direction at the interval’s stated confidence level. The registry does not specify a confidence level for these recalculated intervals in the outcome entries, so the estimates should be read as uncertainty summaries rather than as a claim of a particular threshold. The unadjusted p-values likewise do not account for testing multiple secondary outcomes.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variation exceeds what a statistical model assumes. It can make standard errors too small if the model does not account for the extra variability, leading to intervals that are too narrow and tests that appear more conclusive than warranted. This concept is especially relevant for count or binary outcomes when the model structure assumes more regularity than the data support. The registry does not report an over-dispersion assessment or a model-based analysis for the primary endpoint, so there is no basis to say whether it occurred in this trial.

The planning illustrations for two secondary outcomes use the observed effect as a starting point, equal allocation, a two-sided significance level of 0.05, and a normal approximation. The displayed rows consider planning for 100%, 75%, and 50% of the observed effect, with participants per arm stated for 80% and 90% power. These are forward-looking planning illustrations, not observed power and not evidence that the trial was originally designed around those effects. Their values depend on the observed estimates, which are uncertain in a small trial. The trial’s own sample-size assumptions are not reported in the registry record.

10. Analyses Reported by the Sponsor

The sponsor-reported primary analysis is a two-sided t-test on final values. It reports a mean difference of 9 and p = 0.001. The posted group means are 48.0 for placebo and 39.0 for iNO, so the lower posted mean is in the iNO group. The registry does not provide a confidence interval for the reported mean difference.

No discrepancy is flagged between the sponsor’s result and a recalculation. The reported analysis therefore remains the main inferential result for the primary endpoint; the sponsor’s own analysis takes precedence when there is a discrepancy. There is no separately posted recalculated primary p-value or interval to set alongside the sponsor’s result. The available information does not establish whether covariates, exclusions, or other analysis choices affected the reported test.

The recalculated analyses apply to selected binary secondary outcomes, not to the primary mean comparison. They use the posted counts and denominators to make simple unadjusted comparisons. They should not be read as replacements for a sponsor analysis of the primary outcome, nor as proof that the primary finding is robust to unreported analysis choices. The registry does not post sponsor-reported analyses for those secondary comparisons.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures and six posted secondary outcomes. It does not report a multiplicity plan, such as a prespecified hierarchy of outcomes, an adjustment to the significance threshold, or a method for controlling the overall error rate. Without that information, the status of the primary endpoint as the sole confirmatory test, and the intended interpretation of secondary tests, cannot be established from the registry record.

In general, testing several outcomes increases the chance that at least one result will appear statistically notable even if none represents a true effect. Adjustment methods can address this issue, but they may change the interpretation of individual p-values. The unadjusted secondary comparisons should therefore be considered exploratory. The reported primary test remains distinct, although the registry does not document how the analysis plan treated the family of outcomes.

Missing-data methods and analysis populations are not reported in the registry record. Enrollment was 33, while the primary outcome has 14 participants in each group. The record does not explain the difference, state whether all randomized infants were included, or identify reasons for absent measurements. The denominators for some secondary outcomes also differ from one another and from the primary outcome. Those differences should not be attributed to a particular cause without documentation.

In general, missing outcome data can affect a comparison if the likelihood of having a recorded outcome is related to treatment assignment or the outcome itself. Methods such as imputation or sensitivity analyses can assess assumptions about missing values, but none is described in the registry record. The analysis cannot therefore be characterized as intention-to-treat, per-protocol, or another specified population. Interim analyses, stopping rules, and a detailed statistical analysis plan are also not reported in the registry record. These gaps limit assessment of selective outcome availability and the prespecification of analyses.

12. 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 reports zero participants with serious adverse events among 13 at risk in the placebo group and zero among 12 at risk in the iNO group. It also reports zero participants with other adverse events among the respective groups at risk. Deaths are listed for 1 participant in the placebo group and 2 in the iNO group. These figures describe recorded counts and denominators; the registry does not provide further detail about event timing, causes, or whether deaths were considered related to treatment.

With small risk sets and no reported serious or other adverse-event participants, the counts do not establish that the groups have the same safety profile or that uncommon harms are absent. The death counts should not be interpreted as a treatment effect without details about causes, timing, follow-up, and the analysis plan. The registry record does not report those details. These safety figures are descriptive and do not support medical advice or a conclusion about safety beyond what was recorded.

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

The primary comparison shows lower posted mean maximum FiO2 in the iNO group than in the placebo group during the 20-minute outcome period. The sponsor-reported two-sided test gives a mean difference of 9 and p = 0.001. This is evidence of a difference in the measured endpoint under the reported test, but it does not quantify the uncertainty around the contrast with a posted confidence interval. Nor does it establish that the difference matters clinically.

The endpoint measures peak inspired oxygen, not the total oxygen exposure over time, duration at particular levels, or later respiratory health. The study summary describes a goal of reducing oxygen exposure, but the posted primary endpoint is maximum FiO2. The result should be interpreted in terms of that measure rather than expanded into claims about unmeasured effects.

The trial is a pilot with 33 enrolled participants, and the primary outcome counts 14 participants per group. The registry does not explain the relationship between these numbers or report the analysis population and missing-data handling. These uncertainties, together with the absence of a reported primary contrast interval and sample-size justification, limit assessment of precision and generalizability.

The secondary comparisons are sparse and unadjusted, with uncertainty intervals that include no difference. They do not establish benefits or harms on the listed clinical outcomes, and they do not independently confirm the primary result. The safety record lists no affected participants for serious or other adverse events in the stated risk sets, and lists deaths in both groups; the limited detail and small counts do not establish comparative safety.

In general, a pilot trial can provide preliminary estimates and identify practical or statistical questions for later work. It is not automatically designed to produce a precise or definitive estimate. The registry does not report its own sample-size rationale, so the intended level of precision cannot be inferred. The result is best understood as a short-term, randomized comparison with a notable reported primary test result and substantial limits on conclusions beyond that endpoint.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its primary outcome is a short-term, continuous measurement, while several secondary outcomes are binary clinical events. Those outcome types require different summaries and invite different questions about precision. The primary result is reported as a difference in means with a t-test; secondary comparisons use counts and recalculated risk differences. Reading both as if they were interchangeable would obscure what each analysis estimates.

The contrast between enrollment and the outcome denominators also highlights why analysis populations matter. A randomized design can protect a comparison from some sources of bias, but interpretation still depends on knowing who was analyzed and how missing outcomes were handled. The registry does not explain the primary outcome counts or the varying secondary denominators. That absence is especially consequential in a pilot-scale study, where a small number of observations can influence estimates.

The secondary outcomes illustrate the challenge of multiplicity. A collection of unadjusted tests should not be read as a set of independent confirmations, especially when no multiplicity approach is reported. The planning illustrations also show why effect-size assumptions matter: projected sample sizes vary according to the fraction of the observed effect used for planning. They are illustrations based on the observed effect, not observed power and not evidence of the original design rationale.

Finally, a statistically small p-value does not settle questions of clinical relevance, precision, or generalizability. The registry reports a primary difference but no confidence interval for that contrast, and the endpoint reflects peak oxygen concentration rather than later outcomes. The trial is therefore useful for teaching how to separate a test result from its uncertainty, its measurement target, and the limits of a small study’s record.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations are specific to the available record. The study is a pilot with enrollment of 33, while the posted primary outcome includes 14 participants per arm. The registry does not explain this difference, identify the analysis population, or state why some participants do not appear in the primary outcome counts. The secondary denominators also vary, with no accompanying account of missingness or exclusions.

The primary endpoint is maximum FiO2 over 20 minutes. It does not directly summarize cumulative oxygen exposure or later clinical outcomes, even though the study summary discusses oxygen exposure and possible later problems. The record posts group endpoint bounds but does not identify their statistical meaning, and it gives no confidence interval for the primary mean difference. The dispersion is described as an interquartile range, but no spread values are posted.

The registry does not report the sample-size justification, analysis-plan details, data-handling methods, model diagnostics, or any sensitivity analyses. It also does not report a multiplicity strategy for the outcome set. These omissions limit evaluation of the primary test’s assumptions and of how the secondary results were intended to be interpreted.

Safety reporting is limited to counts and risk sets. Details about the nature, timing, severity, and relatedness of events and deaths are not reported in the registry record. The record also does not specify masking procedures or the identities of the four masked levels. These gaps do not show that the trial was poorly conducted; they limit what can be verified from the registry information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Inhaled Nitric Oxide (iNO) as an Adjunct to Neonatal Resuscitation — NCT01220687.
• Registry record last updated 2020-08-19; status last verified 2020-08.
• Results first posted 2020-08-19.
• 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.

19. Record Summary

NCT01220687, Inhaled Nitric Oxide (iNO) as an Adjunct to Neonatal Resuscitation, is a completed randomized, quadruple-masked, parallel pilot trial sponsored by the University of Oklahoma. Enrollment was 33. It compared inhaled nitric oxide at 20 ppm with nitrogen at 20 ppm during neonatal resuscitation.

The primary outcome was mean maximum FiO2 over 20 minutes. The posted group means were 48.0 for placebo and 39.0 for iNO. The sponsor-reported two-sided t-test gives a mean difference of 9 and p = 0.001; no confidence interval for that contrast is reported. Secondary outcomes include neonatal complications and care measures, with limited results and no reported multiplicity plan. The registry does not report the analysis population, missing-data methods, sample-size justification, or detailed safety-event context.