Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction (NCT02262078), a randomized phase 2 study. The primary outcome is Change in Pulmonary Capillary Wedge Pressure During Exercise.

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel-group phase 2 study sponsored by Mayo Clinic. The registry record lists an enrollment of 26 and a completed status. The study began in 2014-10, and primary completion was recorded in 2015-12. The record does not report the date of final study completion.

The two interventions were sodium nitrite inhalation solution and placebo saline. Both were administered by inhalation with a nebulizer over 10-15 minutes. The stated purpose was to assess the effects of nebulized inhaled nitrite on resting and exercise hemodynamics in patients with HFpEF referred to the catheterization laboratory. The record describes the trial as randomized and quadruple-masked, but does not give further details about the randomization procedure or which roles were masked.

The primary endpoint was a continuous measure: change in pulmonary capillary wedge pressure during exercise. The record reports a mean and standard deviation for each arm. The placebo arm had 13 participants, with a mean change of -1.0 and standard deviation of 2.0 millimeters of mercury. The sodium nitrite arm had 13 participants, with a mean change of -4.0 and standard deviation of 3.0 millimeters of mercury. These are endpoint summaries, not a description of the full study population.

The registry record does not report the planned sample-size justification, the trial’s original statistical assumptions, or additional details of the analysis plan. It also does not provide characteristics that would show how representative the enrolled participants were of other people with HFpEF.

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: Of 70 patients screened, 32 were excluded based upon entry criteria and 12 were excluded based on hemodynamic criteria for Heart Failure with preserved Ejection Fraction (HFpEF) (n=10) or because arterial pressures were too low (n=2).

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 Change in Pulmonary Capillary Wedge Pressure During Exercise, measured over Baseline, after study drug dosing, approximately 4 minutes after starting exercise.

Pulmonary capillary wedge pressure is a measure of cardiac filling pressure. The registry describes it as measured in millimeters of mercury. The primary endpoint was the change in this pressure during exercise, with measurements at baseline and after study drug dosing, approximately 4 minutes after starting exercise.

Studying a change from baseline focuses the comparison on how the measured pressure shifted over the specified period, rather than only comparing the final measurements. Measuring during exercise addresses hemodynamics under the exercise conditions used in the catheterization laboratory. The registry’s stated study aim was to assess resting and exercise hemodynamics in patients with HFpEF, although the posted primary endpoint is specifically the change during exercise.

A lower or more negative change represents a larger decrease from baseline on this change scale. The mean change was -4.0 millimeters of mercury in the sodium nitrite arm and -1.0 millimeters of mercury in the placebo arm. These summaries describe the measured endpoint in the study groups; they do not by themselves establish how the result translates to symptoms, daily function, or longer-term outcomes. Such outcomes are not reported as primary endpoints in the registry record.

The registry record does not report details about the measurement procedure beyond the endpoint definition and timing, or explain how repeated measurements were handled. Interpretation therefore remains tied to the specific exercise measurement and time point stated in the record.

7. Results Posted in the Registry

• Sodium Nitrite: mean -4.00 versus -1.00 on control; difference -3.00 (95% CI -4.96 to -1.04), standardized effect d = -1.18; z-test p = 0.003.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant’s change in pulmonary capillary wedge pressure is measured on a numeric scale. The registry reports the mean and standard deviation in each arm. A mean describes the group’s average change; a standard deviation describes how dispersed individual changes are around that mean. These statistics answer different questions and should not be interchanged.

What does the mean difference represent?

The comparison is the mean change in the sodium nitrite arm minus the mean change in the placebo arm. The unadjusted recalculation is -3.0 millimeters of mercury. Because lower values on this change scale are more negative, the estimate indicates a larger average decrease in the sodium nitrite group. It is a comparison between group averages, not a statement that every participant’s pressure changed by that amount or in the same direction.

The recalculation uses the posted arm summaries and is unadjusted. It is not a substitute for an analysis that might account for design features or covariates under a prespecified model. The registry’s reported analysis is a two-sided t-test. A t-test compares group means while using the observed variability and sample sizes to assess uncertainty. The record does not describe additional adjustment variables or the exact computational details of the sponsor’s test.

How should the p-value be read?

The reported p-value is 0.002, and the unadjusted recalculation is 0.003. A p-value is calculated under a null hypothesis, commonly that the groups have the same mean, and describes how unusual data at least as discrepant as those observed would be under that model. A small p-value does not give the probability that the null hypothesis is true, measure the probability that the result is due to chance, or quantify clinical importance. It also does not establish that the result will be reproduced in another study.

The test is two-sided, so it considers departures in either direction rather than only a decrease. The registry record does not report the assumptions checked for the t-test, such as the distribution of individual changes or the handling of unusual values. General statistical context: t-tests rely on assumptions about the observations and the sampling distribution of the means. With modest group sizes, those assumptions and the observed variability can matter to the precision of the comparison.

Why does variability matter?

The standard deviations are 2.0 millimeters of mercury in the placebo arm and 3.0 millimeters of mercury in the sodium nitrite arm. Greater spread among individual changes generally makes a group mean less precise when the number of observations is unchanged. The recalculation uses a pooled standard deviation of 2.55 for its standardized effect summary, but the mean difference in the original measurement scale is more directly interpretable for this endpoint. Standardized effects express a difference relative to variability; they do not replace the original-unit estimate.

General statistical context: over-dispersion means that observations vary more than a particular model expects. If present, it can make model-based standard errors too small and tests too optimistic unless the analysis accounts for it. The registry record does not report an over-dispersion assessment, and the continuous endpoint and posted summaries do not establish that such a problem occurred.

What does the confidence interval add?

The unadjusted 95% confidence interval for the mean difference extends from -4.96 to -1.04 millimeters of mercury. A confidence interval conveys the precision of an estimate by showing a range of values compatible with the data and the calculation’s assumptions. It is not a range containing a stated proportion of individual participant changes, nor does it incorporate unreported design or measurement uncertainty.

The interval and p-value are related: the reported interval excludes zero, and the recalculated two-sided p-value is small. Neither summary communicates whether the magnitude is important to patients or whether it is sustained. Those questions require clinical context and outcomes not reported in this endpoint record.

What remains unspecified?

The registry record does not report the original sample-size calculation, an interim analysis plan, an analysis population, missing-data procedures, or model diagnostics. It does not say whether there were protocol deviations or how such deviations were handled. These omissions limit the ability to evaluate whether the posted analysis fully follows the trial’s intended statistical plan. They do not change the arithmetic description of the posted group means, but they restrict conclusions about analysis robustness and generalizability.

10. Confidence Intervals and Precision

The unadjusted 95% confidence interval for the mean difference in change is -4.96 to -1.04 millimeters of mercury. The point estimate is -3.0 millimeters of mercury. The interval describes uncertainty in the estimated difference under the recalculation’s assumptions; it is not a prediction interval for individual participants and does not show the range of all plausible individual responses.

Because both endpoints of the interval are negative, the interval does not include a mean difference of zero. The interval’s limits also show that the estimate is not known with perfect precision: values across the reported range remain compatible with the calculation. The trial’s arm-level standard deviations were 2.0 in the placebo arm and 3.0 in the sodium nitrite arm. Individual variability is distinct from the uncertainty around a group comparison, though variability contributes to that uncertainty.

The registry’s own analysis reports p = 0.002, while the unadjusted recalculation reports p = 0.003. The registry does not post a confidence interval for the sponsor’s comparison. The recalculated interval should therefore be understood as accompanying the unadjusted summary-statistic calculation, not as a sponsor-reported interval or an adjusted estimate.

Confidence intervals address sampling uncertainty as represented by the method. They do not resolve possible limitations from measurement procedures, missing outcomes, analysis choices, or participant selection when those details are not reported. The record does not provide further information to quantify those sources of uncertainty.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning estimates are participants per arm, not total events. The registry’s outcome is continuous, so the estimates describe participants per arm for 80% power and participants per arm for 90% power. They are planning illustrations based on the observed effect, not the trial’s own original design calculation.

The assumptions for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. The registry record does not report the assumptions used in the trial’s original sample-size justification.

At 100% of the observed effect, the illustration gives 12 participants per arm for 80% power and 16 participants per arm for 90% power. At 75% of the observed effect, the corresponding estimates are 21 and 27 participants per arm. At 50% of the observed effect, they are 46 and 61 participants per arm. These are hypothetical planning figures under the stated assumptions, not evidence that a future study would attain that power.

The 80% power column represents a planning target for the chance of detecting the selected effect under the assumed model if that effect is real. The 90% column applies a higher target for detection and therefore calls for more participants at each listed effect fraction. Smaller effects need more participants to distinguish them from random variation at a given significance level and power target.

These estimates are not observed power. Observed power is not a useful substitute for interpreting the study’s estimated effect, confidence interval, and uncertainty after the data have been collected. The planning illustrations depend on the observed effect, which is itself uncertain, so they should be treated as scenario-based design guidance rather than a forecast of replication.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -3.000; pooled standard deviation σ = 2.550.
2. n = 2 × (1.96 + 0.842)² × 2.550² / -3.000² = 11.3, rounded up to 12 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -3                      # observed difference in means
sigma <- 2.54950975679639                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2262078)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 12 (80% power), 16 (90% power)
 75% of observed effect: n per arm = 21 (80% power), 27 (90% power)
 50% of observed effect: n per arm = 46 (80% power), 61 (90% power)
power.t.test: 12.4 
Simulated power at n = 12 per arm: 0.786 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparison as a two-sided t-test with p = 0.002. The unadjusted recalculation from the posted group summaries gives a mean difference of -3.0 millimeters of mercury, a 95% confidence interval from -4.96 to -1.04, and p = 0.003. The two p-values are close but not identical.

The registry does not report a confidence interval or test statistic alongside the sponsor’s p-value, and it does not give enough analytic detail to identify why the p-values differ. The recalculation is an unadjusted analysis based on the posted summary statistics; it should not be treated as a reconstruction of every step in the sponsor’s analysis. The registry record does not indicate a discrepancy requiring the recalculation to take precedence. For the sponsor’s analysis, the reported result remains p = 0.002.

The numerical comparison should be read together with the endpoint means and the uncertainty around the recalculated estimate. Neither p-value states the clinical importance or durability of the observed change. The record also does not report further analyses that would establish whether the result is robust to alternative models or analysis populations.

14. Multiplicity, Missing Data and Analysis Populations

The registry record reports one primary outcome measure and one analysis. It does not report secondary outcomes in the posted results. This does not establish that the study had no additional planned analyses; the registry record does not provide enough information to determine the full set of outcomes or tests specified in the protocol and statistical analysis plan.

Multiplicity arises when several hypotheses or endpoints are tested. If many tests are performed, the chance of at least one small p-value can increase unless the analysis plan accounts for that testing. General statistical context: procedures such as adjusting significance thresholds or controlling a family-wise error rate can address some forms of multiplicity. The registry record does not report whether such procedures were planned or used, so no adjustment should be assumed.

The record also does not report an analysis population definition, such as whether participants were analyzed according to assigned group or according to treatment received. It does not report how missing endpoint measurements were handled, whether any endpoint values were missing, or whether sensitivity analyses were undertaken. These details matter because exclusions and missing-data choices can affect the estimated group comparison and its precision.

No interim analyses or stopping rules are reported in the registry record. This should be read as an absence of information in the record, not evidence that no interim monitoring occurred. Similarly, the original statistical analysis plan and protocol details are not reported. The posted t-test and p-value allow the primary comparison to be described, but they do not answer whether all planned analyses were conducted or how deviations from a planned analysis were managed.

These missing details do not alter the reported means, but they limit assessment of selective reporting, analysis robustness, and the relation between the posted analysis and the study’s prespecified plan.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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 reports zero serious adverse events in the placebo arm and zero in the sodium nitrite arm. Each arm had 13 participants at risk in the serious adverse event summary. No serious adverse event terms are listed.

The record separately reports one other adverse event in each arm, with 13 participants at risk in each. These are listed as other adverse events, not serious adverse events. The registry record does not provide event descriptions in the posted summary, so their nature and clinical significance cannot be characterized from these figures.

These counts describe the events recorded in this study; they do not establish that no adverse effects occurred or that the interventions have equivalent safety. A small study may not detect uncommon events, and the record does not provide further detail about surveillance, event definitions, severity, relatedness, or duration. Death counts are not reported in the registry record. The safety figures should therefore be read as limited event summaries, not as a comprehensive assessment of risk.

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

The posted primary result is an acute comparison of change in pulmonary capillary wedge pressure during exercise. Mean change was -4.0 millimeters of mercury in the sodium nitrite arm and -1.0 millimeters of mercury in the placebo arm. The unadjusted mean difference was -3.0 millimeters of mercury, with a 95% confidence interval from -4.96 to -1.04. The registry’s two-sided test reported p = 0.002; the unadjusted recalculation reported p = 0.003.

These statistics describe the observed hemodynamic endpoint in the enrolled groups at the stated measurement time. They do not establish whether the change lasted beyond the acute assessment, affected symptoms or exercise capacity, or altered other clinical outcomes. The registry record does not report those results as part of the posted primary outcome.

A statistically distinguishable group average is not automatically a clinically important difference. The record does not provide a threshold for a meaningful change in pulmonary capillary wedge pressure, nor does it connect the observed difference to patient-centered outcomes. The endpoint is a measure of cardiac filling pressure, not a direct measure of how participants felt or functioned.

The findings also should not be generalized without qualification. The study involved patients with HFpEF referred to a catheterization laboratory, and the registry does not report detailed eligibility criteria or participant characteristics. The small arm sizes and absence of longer-term outcome information limit the scope of conclusions that can be drawn from the posted result.

The result supports a description of the measured acute group difference; it does not establish overall benefit, lack of benefit, or a treatment recommendation. Such broader conclusions are not established by this endpoint and registry record alone.

17. Why This Trial Matters Statistically

This trial illustrates how a physiologic endpoint can be analyzed as a continuous outcome. The interpretation depends on more than the direction of the group means: the measurement scale, the variability within each arm, the estimated between-arm contrast, and its uncertainty all contribute. Here, the mean changes and standard deviations provide context for the recalculated difference and confidence interval.

The comparison also shows why a p-value should not be read in isolation. The registry’s test result and the unadjusted recalculation both indicate a small p-value, while the mean difference and its interval communicate the estimated magnitude and precision in the endpoint’s original units. Those statistics describe the data in different ways; none alone addresses clinical importance.

Planning estimates further demonstrate the relationship between effect size and study size. Under the stated illustrative assumptions, planning for a smaller fraction of the observed effect requires more participants per arm. Because the observed effect is uncertain, these estimates are scenarios for design thinking, not evidence about the likelihood that a new study will reproduce the result.

Finally, the record illustrates the importance of reporting context. Details about missing data, analysis populations, multiplicity, interim monitoring, and the original sample-size rationale are not reported. Their absence limits evaluation of how the primary analysis fits into the full study plan. Clear reporting of such details helps readers distinguish the result itself from assumptions needed to assess its reliability and scope.

18. 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 record offers limited information about the participants beyond the intended population of patients with HFpEF referred to a catheterization laboratory. Eligibility criteria, baseline characteristics, and reasons for referral are not reported. This makes it difficult to assess how closely the enrolled participants resemble other people with HFpEF.

The reported primary outcome is an acute hemodynamic measurement during exercise, approximately 4 minutes after exercise began and after study drug dosing. The record does not report later measurements or clinical outcomes that would show whether the observed change persisted or related to how participants felt or functioned. The result is therefore specific to the stated measurement conditions.

Although the study is described as randomized and quadruple-masked, the registry record does not describe allocation procedures, masking roles, or whether masking was maintained. It also does not report adherence, protocol deviations, measurement reproducibility, or details of how the exercise procedure was standardized.

The posted sample sizes are modest, and the record does not report the trial’s original sample-size justification. Missing-data procedures, analysis-population definitions, interim analyses, and the broader multiplicity plan are also not reported. These omissions make it harder to evaluate the analysis against its prespecified plan and to assess the influence of unreported analytic choices.

The safety summary is limited: it reports event counts but not descriptions of the other adverse events, event severity, relatedness, or death counts. The available figures cannot support a comprehensive comparison of safety. These limitations are specific to what the registry record reports and should be considered alongside the acute nature of the endpoint and the restricted study population.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction — NCT02262078.
• Registry record last updated 2017-08-29; status last verified 2017-07.
• Results first posted 2017-01-19.
• 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.

22. Record Summary

NCT02262078 is a completed randomized, quadruple-masked, parallel-group phase 2 study sponsored by Mayo Clinic. It evaluated inhaled sodium nitrite against saline placebo in patients with HFpEF referred to a catheterization laboratory. Enrollment was 26; the reported endpoint summaries include 13 participants in each arm.

The primary endpoint was change in pulmonary capillary wedge pressure during exercise. Mean change was -4.0 millimeters of mercury with sodium nitrite and -1.0 millimeters of mercury with placebo. The registry reports a two-sided t-test p-value of 0.002. The unadjusted recalculation gives a mean difference of -3.0, with a 95% confidence interval from -4.96 to -1.04 and p = 0.003.

The record reports zero serious adverse events in each arm and one other adverse event in each arm. Further details on participant characteristics, missing data, analysis populations, and the trial’s original statistical plan are not reported in the registry record.