Inhaled Nitric Oxide in Brain Injury: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Nitric Oxide in Brain Injury (NCT03260569), a randomized phase 3 study. The primary outcome is PaO2.

2. Clinical Question

3. Trial Design

The registry describes a completed phase 3 study with randomized allocation, triple masking and a parallel-group model. The sponsor was the University of Cincinnati. The recorded study start date was 2018-12-12, and the primary completion date was 2023-12-28. The registry lists enrollment as 13.

The two treatment groups were inhaled nitric oxide and placebo. The inhaled nitric oxide group received 20 parts per million once during the first 36 hours following admission. The placebo group received nitrogen only, once during the same stated period. The outcome results list 6 participants in the inhaled nitric oxide group and 7 in the placebo group.

Randomized allocation means participants are assigned to groups through a random process, while a parallel design compares groups receiving different assigned interventions. Triple masking indicates that the registry classifies the trial as triple-masked, but it does not identify which roles were masked or describe how masking was maintained. The allocation procedure, masking details, eligibility criteria and setting are not reported in the registry record.

The study summary describes an interest in respiratory mechanics and gas exchange following traumatic brain injury. The posted primary outcome is a continuous measure of PaO2 at Day 3. The registry lists one outcome measure and one analysis, with no secondary outcomes posted. Further protocol details, including how the endpoint was selected and whether other measures were collected, are not reported in the registry 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

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 PaO2, measured over at Day 3 of the study.

PaO2 is a measure of the partial pressure of oxygen, reported in mmHg. It is used to characterize oxygen in the blood and, in this study, to assess gas exchange after traumatic brain injury. The registry identifies the primary endpoint as the difference in PO2 and specifies measurement at Day 3 of the study.

Because PaO2 is continuous, results can be described using group means and a measure of within-group variation. The posted results give means and standard deviations for both groups. The inhaled nitric oxide group had a mean of 115.0 mmHg and a standard deviation of 10.0; the placebo group had a mean of 95.0 mmHg and a standard deviation of 10.0. These summaries describe the observed groups at the specified assessment time. They do not, by themselves, convey the precision of a between-group estimate.

The registry does not report a confidence interval for the endpoint comparison, nor does it provide a detailed measurement protocol or explain how missing Day 3 measurements were handled. Those details would help readers assess how the outcome was obtained and how completely the reported results represent the randomized groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the reported t-test assess?

A t-test is a method for comparing means. In this trial, the registry reports a two-sided t-test for the continuous PaO2 endpoint between the inhaled nitric oxide and placebo groups. A two-sided test considers departures in either direction from the null hypothesis of no difference in group means. The reported result is p <0.05. The registry does not provide the test statistic, exact p-value, or confidence interval.

In general, a t-test evaluates the observed difference in means relative to the variability and amount of information in the data. The standard deviations describe how spread out individual measurements were within each group; they are not standard errors and are not confidence limits. The reported standard deviations are 10.0 in both groups, while the outcome group sizes are 6 and 7. The registry does not state whether the test used a pooled-variance form, a version allowing unequal variances, or another implementation, so its precise assumptions cannot be verified from the record.

How should the p-value be read?

In general, a p-value is calculated under a null model and the assumptions of the statistical test. It describes the compatibility of data at least as extreme as those observed with that model. It does not measure the probability that the treatment has no effect, the probability that the finding will replicate, or the clinical importance of the observed difference. A threshold result such as p <0.05 does not show how large or precise the between-group effect is.

A confidence interval would help describe the uncertainty around an estimated mean difference by giving a range of values compatible with the data and method. No confidence interval or numerical estimate of the comparison is reported in the registry record. As a result, the uncertainty around the comparison cannot be characterized directly from the posted inferential statistics.

Why do group sizes and variability matter?

In general, estimates based on smaller groups tend to be more sensitive to individual observations, and their uncertainty may be substantial. Standard deviations describe variation among observed measurements, while the amount of information available for estimating a mean also depends on the number of observations. The registry provides the group sizes and standard deviations but not individual participant data, distributional summaries, or diagnostic checks. It is therefore not possible to assess whether the test’s assumptions were well supported or whether unusual observations influenced the result.

Over-dispersion is a general concern when the observed variability is greater than a statistical model allows for. If that occurs, standard errors from the model can be too small and inferential results may appear more precise than they are. The registry reports standard deviations but does not describe a model-based dispersion assessment. There is no basis in the record to conclude that over-dispersion occurred in this trial; it is a general issue to consider when evaluating statistical assumptions.

What do the planning illustrations mean?

In general, sample-size planning asks how many participants would be needed under specified assumptions to detect an effect with a chosen level of power. The planning assumptions described for this record use a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such values are planning illustrations, not evidence about the power actually achieved in the completed trial. They are not observed power and do not replace a confidence interval for the trial’s estimated effect.

Planning based on an observed effect can be optimistic if that observed effect is unstable, particularly when the trial is small. A planning illustration also depends on its assumptions about allocation, significance level and the effect to detect. The registry does not report the trial’s original sample-size justification or enough detail to determine whether the planning assumptions match the original design. Any planning figures should therefore be interpreted as hypothetical calculations under stated assumptions rather than as a description of the trial’s own design process.

What cannot be checked from the registry entry?

The record does not report a confidence interval, an adjusted estimate, or the exact p-value. It also does not describe the analysis population, missing-data procedures, model diagnostics, or handling of protocol deviations. The record reports the method as a two-sided t-test but does not give enough implementation detail to reproduce or fully assess that test. These omissions limit independent evaluation of the strength and precision of the comparison.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Inhaled Nitric Oxide", "Placebo")
n   <- c(6, 7)
m   <- c(115, 95)
sp  <- c(10, 10)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Inhaled Nitric Oxide  6  115.000  10.000  104.506  125.494
CARM  Placebo  7  95.000  10.000  85.752  104.248

11. Analyses Reported by the Sponsor

The registry reports the sponsor’s analysis as a two-sided t-test with p <0.05. The reported group means and standard deviations are 115.0 and 10.0 for inhaled nitric oxide, and 95.0 and 10.0 for placebo. The record does not give a numerical estimate for the between-group comparison, a test statistic, or a confidence interval.

No recalculated inferential comparison is available in the registry record to place alongside the sponsor’s test. As a result, there is no second estimate or p-value to compare with the sponsor-reported result. The sponsor’s result remains the only inferential comparison reported for the primary endpoint, but its precision cannot be judged from a confidence interval because none is reported.

Even when a test result is reported as meeting a threshold, the group summaries and inferential result answer different questions: the means describe the observed groups, while the test evaluates compatibility with a null model under its assumptions. Neither supplies information that the registry omits, such as missing-data handling, the analysis population, or the details of test implementation.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and one analysis, and it posts no secondary outcomes. This describes the results entered in the registry record; it does not establish whether other outcomes or analyses were considered during the study. Whether multiplicity was addressed, and by what procedure, is not reported in the registry record. Interim analyses and any associated decision rules are also not reported in the registry record.

The analysis population is not specified. The record does not state whether the reported results include all randomized participants, only participants with an available Day 3 measurement, or another defined group. It also does not describe how missing outcome measurements were handled, whether participants were excluded from the analysis, or how protocol deviations were treated. These details matter because the analyzed set and missingness assumptions can affect the interpretation of a group comparison.

The registry reports outcome group sizes of 6 for inhaled nitric oxide and 7 for placebo. It does not explain whether these counts reflect all randomized participants or only those with evaluable endpoint data. No participant flow, reasons for missing measurements, or sensitivity analyses are reported. The posted summaries therefore cannot establish whether missing data or exclusions influenced the result.

The registry does not report a prespecified statistical analysis plan or explain whether the t-test was the only planned analysis. It is not possible to determine from the record whether the reported test was selected before or after examining the data, or whether any other analyses were performed but not posted. These are reporting limitations, not evidence that particular analyses or procedures did or did not occur.

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 0% reporting threshold.

The registry reports zero serious adverse events in the inhaled nitric oxide group, with 6 at risk, and zero in the placebo group, with 7 at risk. It also reports zero other adverse events in each group, with the same respective numbers at risk. These entries describe the adverse-event counts posted in the record; they do not establish that no events occurred outside the registry’s recorded categories or reporting period.

Deaths are reported separately: 3 in the inhaled nitric oxide group and 2 in the placebo group. The registry does not state whether these deaths were counted among serious adverse events, give their causes or timing, or describe any relationship to study treatment. The adverse-event record does not provide further detail about event definitions, collection procedures, follow-up duration, or adjudication. The serious and other adverse-event entries should therefore be read separately from the death counts, without assuming overlap or cause.

With the limited group sizes and sparse safety detail reported, these figures do not by themselves establish comparative safety. The registry record does not report additional context needed to interpret the deaths or the scope of adverse-event surveillance.

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

The posted results describe PaO2 at Day 3 in the two randomized groups. The inhaled nitric oxide group had a reported mean of 115.0 mmHg, and the placebo group had a reported mean of 95.0 mmHg. The sponsor reports a two-sided t-test with p <0.05. These findings characterize the observed endpoint results and the sponsor’s statistical test; they do not provide a confidence interval or a numerical estimate of the mean difference.

The result does not establish the precision of the comparison. A confidence interval would show how uncertain the estimated difference is under a specified method, but none is reported. The registry also does not provide enough information to judge the impact of missing data, verify the analysis population, or evaluate all assumptions of the t-test. Those limitations are especially relevant when interpreting results from groups with the reported sizes.

The endpoint concerns PaO2 at one specified assessment time. It does not, on its own, describe all aspects of respiratory mechanics, gas exchange, or outcomes following traumatic brain injury. No secondary outcomes are posted, and the registry does not give results for other time points or outcomes. The record also does not provide information that would support conclusions about longer-term outcomes or other populations.

The safety figures are separate from the primary efficacy endpoint. Zero serious adverse events and zero other adverse events are recorded in both groups, while deaths are reported separately. The record does not provide causes, timing or treatment relationships for deaths, so their meaning cannot be inferred from the counts alone. Overall, the registry supports a narrow description of the reported Day 3 summaries, sponsor test and safety counts, with substantial limits on precision and context.

15. Why This Trial Matters Statistically

This trial illustrates why a reported p-value should be considered alongside the estimated effect and its uncertainty. The registry gives group means, standard deviations and a sponsor-reported test, but no confidence interval or numerical estimate of the mean difference. Without an interval, readers cannot see the range of effects compatible with the data under a specified method or gauge the precision of the comparison.

The record also shows how design labels and outcome summaries do not replace detailed reporting. Randomized allocation, triple masking and a parallel design describe important features of the trial, but the registry does not describe the allocation procedure, masking roles, analysis population or missing-data approach. Those details are needed to understand how the design was carried through to the reported analysis.

Small group sizes make transparent reporting of uncertainty and analysis choices particularly useful. Standard deviations provide information about observed variability, but they do not reveal how robust the estimated comparison is to individual measurements. A reported significance threshold alone cannot answer that question.

Finally, the safety entries demonstrate the value of separating event counts from their interpretation. Serious and other adverse events are listed separately from deaths, but the record does not describe causes, timing or overlap. Clear definitions and participant-level context would be needed for a fuller statistical reading. These issues make the trial useful for examining the distinction between observed summaries, inferential evidence and the information required to assess reliability.

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 registry reports enrollment of 13 and outcome groups of 6 and 7. These group sizes limit the amount of information available for estimating a between-group comparison. The record gives standard deviations but no confidence interval, standard error, test statistic, or numerical estimate of the comparison. The precision of the result therefore cannot be evaluated directly from the reported inferential statistics.

Several details needed to assess the analysis are not reported in the registry record: the analysis population, handling of missing Day 3 measurements, treatment of protocol deviations, test implementation, and diagnostic checks. The record does not state whether the t-test assumed equal variances. It also does not report an adjusted analysis or enough detail to assess whether adjustment was used.

The primary outcome is reported at Day 3, but the measurement procedure and endpoint collection details are not given. Eligibility criteria, baseline outcome values, participant flow, reasons for missing data and the original sample-size justification are not reported. Although the record identifies a randomized, triple-masked, parallel design, it does not describe sequence generation, concealment or the roles covered by masking.

The record posts no secondary outcomes and does not report whether multiplicity was addressed, whether interim analyses occurred, or whether other planned outcomes were collected. Safety reporting is also limited: the event entries lack definitions and context, and the deaths have no reported causes, timing or treatment relationship. These gaps prevent a fuller assessment of the result’s precision, robustness and safety context.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Inhaled Nitric Oxide in Brain Injury — NCT03260569.
• Registry record last updated 2025-04-30; status last verified 2025-04.
• Results first posted 2025-04-30.
• 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

The registry describes a completed phase 3 randomized, triple-masked, parallel trial sponsored by the University of Cincinnati. It lists traumatic brain injury as the condition and enrollment as 13. The intervention was inhaled nitric oxide at 20 parts per million once during the first 36 hours following admission; the placebo was nitrogen only, administered once during that period.

The primary endpoint was PaO2 in mmHg at Day 3. The reported means were 115.0 for inhaled nitric oxide and 95.0 for placebo, with standard deviations of 10.0 in both groups. The sponsor reported a two-sided t-test with p <0.05. No confidence interval or numerical comparison estimate is reported.

The registry lists zero serious and zero other adverse events in both groups, and separately reports 3 deaths in the inhaled nitric oxide group and 2 in the placebo group. The record does not provide further context for those deaths or detailed analysis and missing-data information.