Inhaled Nitric Oxide for Preventing Progression in COVID-19: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Nitric Oxide for Preventing Progression in COVID-19 (NCT04388683), a randomized phase 2 study. The primary outcome is Number of Participants With Average Maximum Disease Severity Assessed Through 28 Days.

2. Clinical Question

The clinical question concerns whether early inhaled nitric oxide, compared with standard care, changes the course of clinical severity among hospitalized patients considered at risk for worsening. The brief summary identifies baseline systemic oxygenation and risk factors as part of the risk description. The registry does not provide further detail about oxygenation thresholds or the operational definition of those risk factors.

The primary outcome is not presented as a single treatment-effect estimate. The registry indicates that the outcome has multiple categories or time points and was not reduced to a single comparison. Consequently, the clinical question can be described from the design and endpoint wording, but the posted record does not support a numerical answer about the difference between groups. It also does not establish whether any observed group pattern would be attributable to treatment rather than chance or other sources of uncertainty.

3. Trial Design

The registry describes a phase 2, randomized, parallel-group investigation with no masking. Its brief summary calls it a pilot randomized controlled investigation with 2:1 allocation and an open-label design. The intervention arm was to receive study drug, and the control arm was to receive standard of care. The record does not explain how the allocation sequence was generated or concealed.

The brief summary describes an investigation in 42 hospitalized patients with COVID-19 who were considered at risk for worsening. The registry enrollment field records 10. These figures are not reconciled in the registry record, so the enrollment field should not be silently substituted for the summary’s stated target or vice versa. The record does not clarify whether the enrollment figure represents participants enrolled before termination, a revised target, or another registry convention.

The study start is recorded as 2020-05-12, and primary completion as 2020-11-23. Its status is terminated. The reason for termination and any consequences for recruitment or follow-up are not reported in the registry record. The primary outcome was assessed through 28 days, with clinical scores collected daily beginning on the day after randomization. Study drug began within 1 hour of randomization, according to the endpoint description.

Other outcomes listed include time to maximum clinical disease severity score, time to maximum outcome severity score, participants in each stage at maximum severity, length of hospital stay, and mortality. The record does not state whether all listed outcomes were collected or analyzed. It reports no analyses, and no inferential results are available to describe the randomized comparison.

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: Please note that 9 participants signed consent forms. However, only 8 participants completed the study because the last patient was consented the morning the study was shut down, so they did complete treatment steps or have data collected for them.

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 Number of Participants With Average Maximum Disease Severity Assessed Through 28 Days, measured over 28 days.

The primary endpoint is titled “Number of Participants With Average Maximum Disease Severity Assessed Through 28 Days.” It is expressed as a count of participants. The accompanying description explains the clinical severity scoring process: before randomization, the worse of two scores measured 2 hours apart was used. Participants eligible for randomization had scores of 1 or 2, and randomization was stratified according to that score. Beginning on the day following randomization, the daily clinical score was calculated as the average of three measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM.

Tracking severity through 28 days can capture the course of illness rather than relying solely on a measurement at a single time. Taking repeated measurements may also give a more representative view of daily severity than relying on a single reading. These are general reasons for repeated outcome assessment; the registry does not state the investigators’ rationale for this endpoint or explain how the recorded categories were to be combined for a treatment comparison.

The endpoint title refers to participants with an average maximum severity, while the description focuses on the schedule for calculating daily clinical scores. The registry does not give the score scale’s complete category definitions or a rule for translating the repeated scores into the reported participant count. It also does not report a group contrast or uncertainty estimate for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a randomized, parallel-group design with no masking. Randomization is intended, in general, to make treatment assignment independent of participants’ baseline characteristics on average. It does not guarantee that groups will be well balanced in a small study, and it does not eliminate uncertainty. The record says randomization was stratified by baseline clinical severity score of 1 or 2. Stratification means that allocation is organized within specified categories; the record does not report the sequence-generation or concealment methods.

What does open label mean?

Open label means the study was not masked. Participants and study personnel may know which treatment was assigned, although the registry does not detail who knew what or when. In general, knowledge of assignment can affect care, reporting, or assessment, particularly when an outcome involves clinical judgment. Standardized scoring and repeated measurements can help make assessment procedures more consistent, but they do not by themselves remove all possible influence. The registry does not say whether outcome assessors were masked or whether any steps were used to limit assessment bias.

How should the severity endpoint be understood?

The endpoint concerns the number of participants with average maximum disease severity assessed through 28 days. The description says the worse of two pre-randomization scores, measured 2 hours apart, was used for eligibility; eligible scores were 1 or 2, and randomization was stratified by that score. After randomization, clinical severity was assessed daily starting the following day, using the average of three measurements taken in 2 hour windows centered at 6AM, 2PM, and 10PM. Repeated assessment produces observations over time for each participant. A summary such as maximum severity compresses that trajectory, so interpretation depends on the scoring scale, the definition of maximum, and the handling of incomplete measurements. The registry does not give all category definitions or report how missing daily scores were handled.

What does a count comparison require?

In general, a count of participants in an outcome category is interpreted relative to the participants assessed in each group and to a clearly defined outcome. A comparison might be expressed as a difference, ratio, or model-based estimate, but the suitable approach depends on the endpoint structure and analysis plan. The registry does not report such an estimate or identify the statistical test or model used. Its note that the primary outcome has several categories or time points and was not reduced to a single comparison means there is no simple primary contrast available to interpret from the record.

A confidence interval, in general, describes the uncertainty around an estimated effect under the assumptions of the analysis. It conveys more than whether a result meets a significance threshold: it indicates which effect values remain compatible with the data and method. No confidence interval is reported for the primary outcome. A p-value, also not reported, would address compatibility with a specified null model and would not by itself describe effect size, clinical importance, or the probability that a treatment works.

What do the planning assumptions mean?

The stated sample-size assumptions describe a planning illustration based on an observed effect, not the trial’s own design justification. They specify a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. Planning calculations ask how much information might be needed under chosen assumptions. They are not observed power and do not establish what the trial could detect after enrollment or termination. Since the registry does not report a single primary comparison or its effect estimate, the assumptions alone cannot be used to judge the amount of information available for that comparison. The registry’s general convention is that time-to-event planning values give the total number of events, using Schoenfeld, while other planning values give participants per arm.

Different analytic choices can be appropriate for different endpoint forms. For example, time-to-event outcomes require attention to event timing and censoring, while categorical outcomes require clear category definitions and a plan for comparing groups. These are general statistical considerations, not descriptions of an analysis performed in this trial. The record lists time-to-event and categorical secondary outcomes, but reports no analyses or model specifications. It does not state whether estimates were adjusted, how uncertainty was calculated, or whether any sensitivity analyses were conducted.

With no reported primary comparison, the central methodological task for readers is to separate the measurement plan from the analysis result. The detailed timing of score collection explains how observations were intended to be obtained. It does not reveal the distribution of scores, the number of participants in each severity category, the effect estimate, or its precision. Those results and the analysis methods are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and multiple secondary outcomes, including severity-related measures, hospital stay, and mortality. When several outcomes, categories, or time points are examined, general statistical practice calls for a prespecified approach to multiplicity. Testing many hypotheses can increase the chance of a nominally unusual result arising by chance. Possible approaches include identifying a primary comparison in advance, adjusting inference across a defined family of tests, or treating secondary findings as exploratory. These are general options; the registry record does not report a multiplicity strategy or a hierarchy of outcomes beyond naming the primary endpoint.

The primary-outcome note says that the endpoint has several categories or time points and was not reduced to a single comparison. This leaves the intended primary contrast unclear in the posted record. The registry also reports no analyses, so it does not show which outcomes or time points were included in any analysis, whether all were analyzed, or how any multiplicity was handled. No interim analyses or stopping boundaries are reported; the record does not establish whether they were planned or conducted.

Missing-data handling is not reported in the registry record. In general, missing clinical scores can affect a maximum-severity summary because unobserved measurements may conceal a participant’s worst recorded state. Interpretation depends on how much information is missing, why it is missing, and the methods used to address it. None of those details are available as registry information.

The analysis population is also not reported in the registry record. It is therefore unclear whether an analysis, if conducted, would include all randomized participants, only participants with outcome data, or another defined group. The difference between the enrollment field and the brief summary’s participant figure further cautions against assuming an analysis denominator. The record does not report a statistical analysis plan, so the prespecified handling of these issues cannot be assessed.

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 posted adverse-event figures record 0 serious adverse events among 6 participants at risk in the intervention group and 0 among 3 participants at risk in the control group. Other adverse events are also recorded as 0 among 6 at risk in the intervention group and 0 among 3 at risk in the control group. Deaths are recorded as 0 for each group. No serious adverse-event terms are listed.

These are descriptive counts, not evidence that the risk of an adverse event is absent. With no recorded events in either group, the figures do not provide a useful estimate of a between-group difference or its precision. The number at risk is limited, and the registry record does not describe event-collection procedures, follow-up completeness, or how adverse events were defined. It also does not clarify whether these figures cover the same follow-up period as the primary endpoint. The counts should therefore be read as the events recorded in the registry, not as a comprehensive safety conclusion.

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

The result described by the registry is chiefly a study record rather than a report of comparative efficacy. It identifies an open-label randomized pilot of inhaled nitric oxide versus standard of care and describes repeated clinical severity scoring through 28 days. It does not provide the primary outcome comparison, group-level severity results, or an uncertainty estimate. The posted information therefore cannot establish the direction or magnitude of a treatment effect.

The absence of a reported comparison should not be interpreted as evidence of no difference. It also should not be treated as evidence that a benefit or harm was present. A conclusion about comparative outcomes requires the observed data, a defined analysis, and an estimate with appropriate uncertainty. These are not reported for the primary endpoint in the registry record.

The trial is described as a pilot, and its status is terminated. The brief summary describes an investigation in 42 hospitalized patients, while the enrollment field records 10; the record does not reconcile those figures. The reason for termination, the final analysis population, and the completeness of follow-up are not reported. These gaps limit what can be inferred about feasibility, precision, and generalizability.

The adverse-event figures record no serious or other events and no deaths in the reported groups, but the small recorded risk groups and lack of ascertainment details prevent a broad safety conclusion. These figures do not answer the primary clinical question and should not be used alone to characterize comparative safety.

In general, randomized assignment supports a fair comparison when allocation and follow-up are implemented appropriately, but randomization does not compensate for unavailable outcome results or unclear analysis choices. The record supports statements about the planned comparison, scoring schedule, status, and recorded event counts. It does not support advice about treatment or a claim that inhaled nitric oxide does or does not change COVID-19 progression.

13. Why This Trial Matters Statistically

This trial illustrates why a registry description and a results analysis answer different questions. The record provides useful design information: randomization, an open-label parallel-group structure, the intervention and comparator, and a repeated clinical severity measurement schedule. Those details help readers understand what investigators intended to compare and how the outcome was to be observed.

At the same time, the primary endpoint is not accompanied by a group comparison. The registry notes that the outcome has several categories or time points and was not reduced to a single comparison. Without a defined contrast and its uncertainty, the endpoint description cannot answer whether the groups differed, how large any difference was, or how compatible the data are with a range of possible effects. This is a central statistical distinction: measuring an outcome is not the same as estimating a treatment effect.

The enrollment information also shows why registry entries need contextual reading. The enrollment field records 10, while the brief summary describes 42 hospitalized patients. Because the record does not reconcile those figures, readers cannot safely infer the final analysis denominator or the degree of information available. The terminated status adds context, but not an explanation of what happened to recruitment or data collection.

The case also emphasizes the value of transparent reporting on analysis populations, missing outcomes, multiplicity, and statistical methods. Those choices affect how an estimate should be interpreted, especially when severity is measured repeatedly and can be summarized in multiple ways. Their absence does not prove that no analysis was performed; it means the registry record does not document one. For biostatisticians and clinical researchers, this distinction is important when assessing what a study record can and cannot support.

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 this trial is that the registry record does not report primary-outcome results or an inferential comparison. It gives the endpoint title and measurement schedule but not the group-level counts, category distributions, effect estimate, confidence interval, or p-value. The endpoint note also says the outcome was not reduced to a single comparison, leaving the intended contrast unresolved.

The enrollment field records 10, whereas the brief summary describes 42 hospitalized patients. The registry does not explain how these values relate to each other. The record also does not report the reason for termination, the number of participants with complete follow-up, or the analysis population. These gaps make it difficult to assess how much information was available for the endpoint or whether the planned assessment was completed.

Although the record gives a detailed schedule for severity scoring, it does not provide full score-category definitions, the rule for summarizing the recorded categories, or the handling of missing measurements. It does not report the statistical analysis plan, the test or model, adjustments, multiplicity procedures, or sensitivity analyses. The open-label design may also leave clinical assessment vulnerable to knowledge of assignment; the registry does not state whether assessors were masked.

The safety counts are limited to the recorded groups and do not include details about ascertainment or follow-up completeness. As a result, they cannot establish the absence of safety risks. Taken together, these limitations mean the record is informative about trial structure and planned measurement but insufficient for estimating comparative clinical outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Inhaled Nitric Oxide for Preventing Progression in COVID-19 — NCT04388683.
• Registry record last updated 2022-04-19; status last verified 2022-04.
• Results first posted 2022-04-19.
• 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

NCT04388683 is a phase 2 randomized, open-label, parallel-group study of inhaled nitric oxide versus standard of care in hospitalized patients with COVID-19. The brief summary describes a 2:1 pilot investigation in 42 patients, while the enrollment field records 10; the registry does not reconcile the figures. The study started on 2020-05-12, has primary completion recorded as 2020-11-23, and is listed as terminated.

The primary endpoint concerns the number of participants with average maximum disease severity assessed through 28 days. Clinical severity was assessed daily beginning on the day after randomization, using averages of repeated measurements. The record does not report a primary comparison or analysis results. The recorded adverse-event figures show 0 serious events, 0 other events, and 0 deaths in each group, with 6 participants at risk in the intervention group and 3 in the control group.