Oral Nitrite in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Oral Nitrite in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction (NCT03015402), a randomized phase 2 study. The primary outcome is Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite.

2. Clinical Question

The trial’s stated objective was to assess the clinical efficacy of oral inorganic nitrite compared with placebo, with attention to therapeutic response in exercise tolerance among people with PH-HFpEF. The primary endpoint narrows that objective to mean pulmonary artery pressure (mPAP) during submaximal exercise. The record describes measurements at baseline and 10 weeks, and identifies the between-intervention comparison at 10 weeks as the primary question.

This is a comparison of two interventions within a randomized crossover study, rather than a simple comparison of two separate parallel groups. In a crossover design, participants receive both interventions at different times. The registry record does not report the treatment sequence or the period-specific details, so those aspects cannot be elaborated. The primary analysis population also has a completion requirement: participants had to receive at least one dose of each intervention and complete all study visits. The registry record does not report how many participants met that definition or the numerical mPAP results for the comparison.

3. Trial Design

The registry record describes NCT03015402 as a phase II, randomized, quadruple-masked, crossover study sponsored by the University of Pittsburgh. The study is marked completed. Its recorded enrollment is 33. The listed conditions are pulmonary hypertension secondary and heart failure. The start date is 2017-10-30, and the primary completion date is 2023-01-25.

The interventions were sodium nitrite and a placebo oral capsule. The record labels sodium nitrite as the study intervention and placebo as the control. Because the design is crossover, participants were intended to receive both interventions, but the registry record does not describe the treatment sequence, the duration of each treatment period, or any washout period. Those details should not be inferred from the design label alone.

Quadruple masking indicates that the record identifies the study as masked at four levels, but it does not specify which roles were masked or how masking was maintained. The registry record also does not report the dosing schedule, adherence procedures, eligibility criteria beyond the conditions and primary population description, or the planned statistical model for the crossover comparison.

The primary efficacy population consisted of participants who received at least one dose of each intervention and completed all study visits. That definition is narrower than simply enrolling in the trial. The record does not state the number included in that analysis or give a participant flow accounting for those who did not meet the definition. The listed secondary outcomes include exercise testing, right heart catheterization hemodynamics, heart failure severity, and endurance exercise time. The registry record gives no numerical results for the primary comparison in the information available for this analysis.

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: A total of 33 subjects were enrolled and consented with 9 screen failed/ineligible and 24 randomized. Of the 24 randomized, 3 were on drug/placebo but withdrew at a later time, and 21 completed the study.

First Intervention (10 Weeks)

Reasons for not completing this period:

Washout (2 Weeks)

Reasons for not completing this period:

Second Intervention (10 Weeks)

Analysis population for the primary outcome, as defined in the registry: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.

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 Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite, measured over Baseline and 10 weeks.

The primary endpoint is mean pulmonary artery pressure during submaximal exercise, expressed in mmHg. The registry describes a comparison between placebo and oral nitrite at 10 weeks, with the broader measurement timeframe listed as baseline and 10 weeks. The outcome is continuous, and the record identifies the summary measure as a mean with standard deviation.

mPAP is a measure of pressure in the pulmonary artery. Measuring it during exercise focuses the assessment on hemodynamics under exertion rather than only at rest. In general, a continuous endpoint can preserve information across the range of observed values, rather than reducing measurements to categories. The mean describes the average level in the analyzed group, while the standard deviation describes how dispersed participant measurements are around that average.

The endpoint was chosen in the context of the stated study objective, which concerns the response to oral nitrite and exercise tolerance in PH-HFpEF. However, the registry record does not report the primary means, standard deviations, treatment contrast, confidence interval, or significance test. It therefore does not support a quantitative statement about the size or precision of the primary comparison. The endpoint definition explains what was intended to be compared, but it is not itself evidence of the direction or magnitude of a result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: mPAP during submaximal exercise, measured in mmHg. The registry record identifies the summary statistic as a mean and the measure of dispersion as a standard deviation. It describes measurements at baseline and 10 weeks and a comparison between placebo and oral nitrite at 10 weeks. It does not report the numerical summaries or the model used to make that comparison.

What does a mean and standard deviation describe?

In general, the mean represents the average of measured values in an analysis group. The standard deviation describes how much individual observations vary around that average. These answer different questions: the mean locates the group’s average, while the standard deviation describes variability among measurements. Neither one alone gives the uncertainty of the estimated treatment contrast. A standard error or confidence interval is commonly used to describe uncertainty in an estimate, but those values are not reported for this primary comparison.

Why does the crossover design matter?

In general, a crossover design compares interventions received by the same participants in different treatment periods. This can allow each participant’s measurements under one intervention to be considered alongside their measurements under the other. Appropriate analysis may need to account for within-participant correlation and for factors such as treatment period or sequence. The record does not report the treatment sequence, period structure, washout details, or statistical model, so it is not possible to determine how those features were handled in the primary analysis.

A simple comparison treating all intervention observations as independent could fail to reflect the paired structure of a crossover study. This is a general methodological point, not a description of the analysis used in this trial. The registry record does not give enough detail to establish whether the analysis accounted for pairing, period effects, or other design features.

How should statistical significance and precision be read?

In general, a p-value evaluates the compatibility of observed data with a null hypothesis under specified assumptions. It does not quantify the size or importance of an effect. A confidence interval gives a range of values compatible with the data and the calculation method; its width conveys precision. A treatment contrast and its interval are usually more informative about magnitude and uncertainty than a significance label alone. The primary result values, p-value, and confidence interval are not reported in the registry record, so these interpretations cannot be applied to a numerical finding from this trial.

The record notes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect described as a stated fraction of the observed effect. These are planning assumptions, not the trial’s own design justification. The numerical planning outputs are not reported in the registry record. Any sample-size values presented as planning illustrations should be understood as hypothetical requirements under those assumptions, not as observed power or evidence about the primary result. Sample-size calculations do not establish that an analysis was adequately powered after the fact.

What can the outcome listing establish?

The registry lists nine outcome measures and one analysis. These entries describe the record’s outcome and analysis listings; they do not provide the missing primary estimate. The primary outcome description gives a measurement and comparison, but not a result. Secondary outcomes include the 6-minute Walk Test, right heart catheterization hemodynamics, heart failure severity, and endurance exercise time. Their listing does not establish what values were observed or whether any comparison was statistically significant.

In general, continuous clinical measurements can have distributions that depart from the assumptions of a chosen model. A suitable analysis should reflect the design, outcome distribution, and dependence among observations. The registry record does not report diagnostic checks, distributional assumptions, transformations, or alternative analyses. Thus the appropriateness of those aspects cannot be evaluated from the recorded details alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists multiple secondary outcomes alongside the primary mPAP endpoint. These include the 6-minute Walk Test, several right heart catheterization hemodynamic measures, heart failure severity, and endurance exercise time. When a study evaluates multiple outcomes or comparisons, the chance of at least one apparently unusual result can increase if each is tested separately. In general, a prespecified hierarchy or an adjustment for multiple testing can help define how such results should be interpreted.

The record does not report a multiplicity strategy, a hierarchy among outcomes, or whether secondary analyses were confirmatory or exploratory. It also does not report whether any interim analyses were planned or conducted. Those details are not reported in the registry record, so no conclusion about multiplicity control can be drawn.

The primary analysis population is defined as participants who received at least one dose of each intervention and completed all study visits. The number included and the number excluded from that analysis are not reported in the registry record. The record does not describe a missing-data method, reasons for missing measurements, or sensitivity analyses. It is therefore not possible to assess how incomplete visits or missing endpoint values may have affected the primary estimate.

In general, analyzing only participants with complete data can lead to bias if completion is related to outcomes or treatment response. Other approaches may use available measurements or assumptions about missingness, but their suitability depends on the study and the missing-data pattern. The record does not identify which approach, if any, was used. It also does not describe handling of crossover-specific missing periods or measurements. These omissions limit assessment of both the analysis population and the robustness of any intended treatment comparison.

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.

Most frequent non-serious adverse event terms

The registry lists safety figures separately for Oral Nitrite and Placebo. For each listed group, 24 participants were at risk for serious adverse events, and 0 serious adverse events were affected. The record also lists 24 at risk for other adverse events in each group, with 22 affected in the Oral Nitrite group and 23 in the Placebo group. Deaths are listed as 0 for both groups.

These figures are counts as recorded; they do not provide event descriptions, severity details for the other adverse events, timing, or a comparison adjusted for the crossover design. The registry’s serious adverse-event terms are not listed. The adverse-event figures alone do not establish whether an event was caused by an intervention.

Because this is a crossover study, the same participant may contribute exposure to both interventions. The group-specific counts should not be read as numbers of distinct participants across the entire study, and the registry record does not explain how event attribution or repeated exposure was handled. The risk denominators are the counts recorded for each intervention group, not a basis for inferring the total number of participants. These safety figures describe what the registry reports and do not, by themselves, establish a comparative safety conclusion.

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

The registry record identifies a focused randomized crossover question: the comparison of mean pulmonary artery pressure during submaximal exercise between placebo and oral nitrite at 10 weeks in PH-HFpEF. It also describes the primary efficacy population and reports selected safety counts. These details help readers understand what the trial set out to measure and how the primary population was defined.

The record does not report the numerical primary outcome comparison. Consequently, it does not show the direction or size of any difference, its precision, or a statistical test result. No conclusion about whether mPAP differed between interventions can be drawn from the endpoint description alone. A completed status indicates the trial is marked completed in the registry, not that the posted record contains enough results to quantify the primary finding.

In general, a measured difference is not automatically evidence of a meaningful clinical effect. Interpretation depends on the estimate’s size, its uncertainty, the clinical context, and how well the study design and analysis support the comparison. Those elements cannot be assessed for the primary endpoint without its numerical results and analysis details. The outcome listing also does not establish findings for exercise tolerance or the secondary hemodynamic measures.

The safety entries show 0 serious adverse events and 0 deaths in each listed intervention group, alongside other adverse events affecting 22 in the Oral Nitrite group and 23 in the Placebo group. These are descriptive counts, not a complete account of event types, timing, attribution, or uncertainty. The crossover design further means the group counts should not be interpreted as separate parallel groups of participants.

Accordingly, the record supports a description of the trial question, design, analysis-population definition, and recorded adverse-event counts. It does not support a conclusion about efficacy, a quantified treatment effect, or a definitive comparative safety assessment.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining a randomized comparison with a crossover design and a continuous exercise hemodynamic endpoint. In general, a crossover approach can make within-participant comparisons possible, while also requiring analysis that respects the paired measurements and treatment periods. The registry record identifies the crossover structure, but does not describe the treatment sequence or the statistical model. That makes the design relevant to interpretation while leaving important analytical details unresolved.

The primary question is specific: mean pulmonary artery pressure during submaximal exercise, compared between placebo and oral nitrite at 10 weeks. The record also places the endpoint in the context of exercise tolerance and lists related outcomes, including walking performance and other hemodynamic measures. This distinction between a clearly defined question and a numerical answer is important: the registry record specifies what the primary comparison concerns but does not report its estimate.

The analysis population definition is another important statistical feature. Requiring receipt of at least one dose of each intervention and completion of all study visits gives a clear eligibility rule for the efficacy analysis. However, the number meeting that rule and the treatment of incomplete data are not reported. Those details matter because a crossover analysis depends on observations from both treatment periods.

The adverse-event record provides counts for serious events, other events, and deaths, but gives limited context for interpreting them. The crossover design also cautions against treating intervention-specific safety counts as if they came from independent parallel groups. Overall, the trial illustrates why design labels and outcome definitions are only part of statistical interpretation: estimates, uncertainty, analysis methods, and participant accounting are also needed.

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 record is the absence of numerical results for the primary endpoint. Although the endpoint, unit, summary measure, timeframe, and analysis-population definition are recorded, the registry does not report group means, standard deviations, a treatment contrast, a confidence interval, or a p-value. The direction, magnitude, and precision of the primary comparison therefore cannot be evaluated.

The record does not describe the crossover treatment sequence, duration of treatment periods, washout arrangements, or the statistical model. It is not possible to establish from the registry record whether the primary analysis accounted for within-participant pairing, period effects, sequence, or other relevant design features. The efficacy-analysis population is defined, but its size, participant flow, and missing-data handling are not reported.

The record lists secondary outcomes but does not give their numerical results or explain a multiplicity strategy. It does not report whether interim analyses occurred, how outcomes were prioritized, or whether secondary analyses were intended as confirmatory. Details about eligibility criteria, dosing, adherence, and the masking procedures are also not reported in the registry record.

Safety information is limited to group-level counts. The serious adverse-event terms are not listed, and the record does not give descriptions, timing, attribution, or details that would permit a fuller assessment of other adverse events. Since the study is a crossover, the group counts should not be treated as counts from independent parallel arms. Together, these omissions restrict assessment of efficacy, statistical robustness, and comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Oral Nitrite in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction — NCT03015402.
• Registry record last updated 2024-06-07; status last verified 2024-06.
• Results first posted 2024-06-07.
• 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

NCT03015402 is a completed phase II randomized, quadruple-masked crossover study sponsored by the University of Pittsburgh. It enrolled 33 participants and compared oral sodium nitrite with a placebo oral capsule in pulmonary hypertension and heart failure with preserved ejection fraction. The recorded start date is 2017-10-30, and the primary completion date is 2023-01-25.

The primary endpoint was mean pulmonary artery pressure during submaximal exercise, measured in mmHg, with the primary comparison described at 10 weeks. The efficacy population was defined as participants who received at least one dose of each intervention and completed all study visits. Numerical primary results and details of the statistical model are not reported in the registry record.

Safety entries list 0 serious adverse events and 0 deaths for each intervention group. Other adverse events were recorded for 22 in the Oral Nitrite group and 23 in the Placebo group. These counts do not provide event descriptions or a complete comparative safety assessment.