Dietary Nitrate for Heart Failure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dietary Nitrate for Heart Failure (NCT01682356), a randomized phase 1, phase 2 study. The primary outcome is Maximal Knee Extensor Power.

2. Clinical Question

The registry’s brief summary describes several research aims, including exercise tolerance, peak power, blood pressure, vascular and muscle function, and nitrate levels after ingestion. The posted primary endpoint is narrower: maximal knee extensor power, expressed in W/kg. The result therefore addresses that measurement in the endpoint population, rather than all the aims listed in the broader study summary.

The registry identifies the study as randomized, double-masked, and crossover. Those labels describe the overall design, but the record does not report treatment sequence details or explain how the crossover structure was handled in the primary comparison. Those details matter when interpreting a treatment contrast because measurements from the same participant may be related.

3. Trial Design

The registry identifies NCT01682356 as a Phase 1 and Phase 2 randomized, double-masked crossover study sponsored by Washington University School of Medicine. The study status is completed, and enrollment is listed as 17. The registry lists heart failure and pulmonary hypertension among the conditions.

The primary endpoint compared nitrate-containing beetroot juice with placebo, described in the arm information as beetroot juice without nitrate. The endpoint timeframe was 2-3 h after an acute dose. The registry reports 9 participants assessed for maximal knee extensor power and gives group summaries for 9 participants in each condition. Since this is a crossover study, those group counts should not automatically be read as independent groups of different people; the record does not describe the individual treatment sequences or the analysis population in enough detail to establish the exact relationship.

The registry’s broader summary describes additional aims and procedures, including a 6-minute walk test, measurement of physiological responses, and investigations related to clinical procedures. It also describes repeat walk testing after at least a 48 hours rest. These details indicate that the research covered more than the posted primary endpoint, but the registry does not report how each aim related to the primary endpoint analysis or which participants contributed to each analysis.

The registry lists a start date of 2012-01 and a primary completion date of 2023-07-01. It does not report the randomization sequence, treatment-period lengths, washout between treatment conditions, or masking procedures in detail. Those features cannot be inferred from the crossover and double-masked labels alone.

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

Analysis population for the primary outcome, as defined in the registry: Only 9 participants were assessed for maximal knee extensor power.

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 Maximal Knee Extensor Power, measured over 2-3 h after acute dose of beetroot juice containing or essentially devoid of nitrate.

The primary endpoint is maximal knee extensor power, reported in W/kg. The registry describes it as maximal power of the quadriceps muscle group measured using isokinetic dynamometry. The stated timeframe is 2-3 h after an acute dose of beetroot juice containing or essentially devoid of nitrate.

In general, a continuous measurement such as power can describe the magnitude of a physical performance measure on a scale, while a comparison between treatment conditions asks whether the observed values differ. The registry reports a mean and standard error for each condition, along with a sponsor-reported test of the comparison. These summarize the posted results, but the mean alone does not describe how much individual participants varied, and the standard error is not a range containing all participant values.

The endpoint is relevant to the study’s stated interest in exercise-related performance, but it is distinct from the other outcomes described in the broader summary, such as the 6-minute walk test, blood pressure, and vascular or muscle function. The registry does not report a clinical threshold for interpreting a change in maximal knee extensor power, or evidence that this measurement by itself represents changes in daily function or other outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is continuous, and the registry reports a mean with standard error for each condition. The sponsor-reported comparison is a two-sided t-test. The record does not provide a confidence interval, a numerical treatment-effect estimate, or details of the test beyond its name and direction.

What does the mean describe?

In general, the mean is a measure of the center of a set of observations. Here, each condition’s reported mean summarizes maximal knee extensor power in W/kg. A mean gives a concise group summary, but it does not show the spread of individual measurements or whether a few observations strongly influence the center. Participant-level values and other distribution summaries are not reported in the registry record.

What does the standard error describe?

In general, a standard error describes the uncertainty in an estimated quantity, such as a mean, under a statistical model. It is not the same as the standard deviation, which describes variability among observations, and it does not indicate the range of values observed among participants. The registry reports standard errors of 0.33 for placebo and 0.41 for nitrate. The record does not report standard deviations or confidence intervals for these means.

What does a two-sided t-test ask?

In general, a two-sided test evaluates evidence for a difference in either direction, rather than specifying only that one condition must be higher. The reported p-value is 0.015. Under the null model and the assumptions of the test, a p-value reflects how unusual results at least as discrepant as the observed result would be. It is not a probability that the null model is true, and it does not provide an estimate of how large the treatment contrast is.

The registry does not report the t-statistic, degrees of freedom, confidence interval, or the exact test formulation. Although the record labels the trial a crossover study, it does not state whether the sponsor’s test was paired or unpaired, nor does it describe how the treatment sequence or period was incorporated. In general, the analysis should reflect the way observations were collected. If the same participants contribute to both conditions, the relationship between their measurements may affect the uncertainty of the contrast. The posted record does not provide enough detail to determine how that relationship was handled.

Why does the crossover design matter?

In general, crossover studies compare conditions within participants, and the resulting observations may be correlated. Such designs can distinguish treatment-condition differences from stable differences between participants, but the analysis needs to account for the study structure. Treatment order, changes over time, carryover between periods, and incomplete participation can also be relevant considerations. The registry record does not report treatment sequences, period-specific summaries, a washout duration, or an analysis of carryover or period effects. These omissions limit an independent assessment of whether the reported test fully reflects the design.

What can be learned from the reported precision?

In general, a confidence interval gives a range of values compatible with the data and the assumptions used to calculate it. Its width communicates the precision of the estimated contrast; it does not guarantee that the true effect lies in the interval. No confidence interval for the primary contrast is reported in the registry record. The group means, standard errors, and p-value therefore do not provide the same information as a clearly specified estimate with an interval.

The sample-size assumptions in the record describe planning illustrations based on an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are not the study’s observed results and are not observed power. No numerical planning values are included in the registry record for this analysis, so no number of participants for a planning scenario can be stated. The registry does not report the trial’s own sample-size justification.

In general, over-dispersion matters when observed variation exceeds what a statistical model assumes, because standard errors and tests based on that model may then be poorly calibrated. The registry does not report a dispersion assessment for this endpoint, and the endpoint is not identified as a count outcome. This general issue therefore should not be mistaken for a finding about the posted power measurements.

Finally, the reported p-value addresses the specified primary comparison only as presented. The registry lists 27 outcome measures and 22 analyses, but it does not explain how those analyses were selected, whether any were prespecified, or how multiple testing was handled. These missing details affect how the primary result should be viewed in the context of the full set of analyses.

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("Placebo", "Nitrate")
n   <- c(9, 9)
m   <- c(4.2, 4.74)
sp  <- c(0.33, 0.41)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
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  Placebo  9  4.200  0.990  3.439  4.961
CARM  Nitrate  9  4.740  1.230  3.795  5.685

11. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparison as a two-sided t-test with p = 0.015. It does not report a sponsor-estimated contrast, confidence interval, test statistic, or further details about the model. The group summaries are means of 4.2 W/kg for placebo and 4.74 W/kg for nitrate, with standard errors of 0.33 and 0.41, respectively.

The record does not flag a discrepancy between the sponsor’s result and a simple recalculation. However, no separately reported recalculated estimate or interval is included in the registry record for this analysis. A recalculation from summary statistics, where available, is unadjusted and may not reflect the crossover design or the sponsor’s participant-level analysis. It should not replace an analysis that accounts for the trial structure.

Because the registry does not specify whether the t-test was paired or how the crossover was incorporated, the relationship between the sponsor’s test and any unadjusted recalculation cannot be fully assessed. The sponsor’s reported analysis remains the stated trial result; the registry record does not provide enough statistical detail to reconstruct its full method.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists 27 outcome measures and 22 analyses, as well as one posted secondary outcome, VO2peak. The primary endpoint discussed in these results is maximal knee extensor power. The record does not provide a complete mapping of the analyses to outcomes or describe which outcomes were prespecified, exploratory, or omitted from the posted results.

In general, multiplicity arises when several statistical tests are considered together. With more opportunities to find a result that appears noteworthy, the interpretation of an individual p-value can depend on the wider testing plan. Methods for addressing multiplicity may adjust the analysis or define a hierarchy of outcomes, but the registry does not report whether such methods were used. The reported p-value should therefore be read as the result of the stated primary comparison, without assuming a particular multiplicity adjustment.

The record does not report how missing observations were handled, whether all randomized participants were included in the primary analysis, or whether the analysis followed an intention-to-treat approach. It reports that 9 participants were assessed for the primary endpoint and lists enrollment as 17, but does not explain the endpoint participation or provide reasons for missing measurements. The analysis population and exclusions are not reported in the registry record.

For a crossover study, incomplete data may affect whether participants contribute observations under both conditions. In general, the handling of such data can influence the comparison and its precision. The registry does not report participant flow by treatment period, the number with complete paired observations, or any imputation approach. These gaps prevent a detailed assessment of missing-data assumptions and the scope of the analyzed population.

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 adverse-event record lists 17 participants at risk in each condition. For placebo, it reports 0 participants with serious adverse events and 0 with other adverse events; for nitrate, it likewise reports 0 participants with serious adverse events and 0 with other adverse events. The record lists 0 deaths in each condition, and no top serious-event terms are listed.

These figures describe the adverse-event entries posted in the registry. They do not by themselves establish that no events occurred outside the recorded definitions or observation period. The record does not specify the adverse-event collection timeframe, severity criteria, attribution procedures, or how the crossover periods relate to the at-risk counts. Since the trial is crossover, the group counts should not be interpreted as necessarily representing separate sets of participants.

In general, a zero count in a small study does not show that an event is impossible or rule out uncommon harms. The posted figures are limited to the participants and reporting framework represented in the record; they are not a substitute for a complete safety analysis.

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

The posted primary result shows a higher mean maximal knee extensor power in the nitrate condition than in the placebo condition, with a sponsor-reported two-sided t-test p-value of 0.015. The endpoint was measured 2-3 h after an acute dose, and only 9 participants were assessed. This is a result for one measurement and one stated timeframe.

It does not establish the size or precision of the treatment contrast because the registry does not report a confidence interval or an estimate of the contrast. The reported p-value does not communicate clinical importance or the probability that the finding is true. The record also does not give sufficient detail about how the crossover design was handled in the analysis, so the reported test cannot be independently reconstructed from the registry information.

The result does not answer every question described in the broader study summary. The summary includes exercise tolerance, blood pressure, vascular and muscle function, nitrate levels, and other investigations. Findings for those questions cannot be inferred from the maximal knee extensor power result. The registry lists VO2peak as a secondary outcome, but its result is not reported in the registry record for this analysis.

Nor does the primary endpoint alone establish that a change in measured power corresponds to a change in daily activity, symptoms, or other clinical outcomes. The registry does not report a threshold for interpreting the measurement or a link between this endpoint and such outcomes. The result should be understood as a statistical comparison of the posted measure, not a conclusion about overall clinical benefit.

The reported adverse-event entries list no serious or other adverse events and no deaths in either condition, among 17 at risk per condition. Those entries provide limited safety information and do not rule out unrecorded or uncommon events. Taken together, the record supports a careful description of the observed endpoint and reported test, while leaving important questions about precision, analysis details, missing data, and other outcomes unanswered.

15. Why This Trial Matters Statistically

This trial is statistically notable because it combines a crossover design with a continuous performance endpoint and a small endpoint population. The registry identifies randomized treatment conditions and reports means, standard errors, and a two-sided test. Those elements allow a reader to distinguish the direction of the observed group summaries from the uncertainty implied by the reported test, while also showing how much analysis detail is missing.

In general, crossover designs raise questions about within-participant comparisons, treatment sequence, and changes over time. Knowing that a study is a crossover trial is not enough to determine whether the reported analysis appropriately models those features. The registry does not state whether the t-test was paired or how the treatment periods were handled. This makes the record a useful example of why a test name and p-value alone do not fully describe an analysis.

The endpoint also illustrates the distinction between statistical evidence and clinical interpretation. A p-value is not an effect-size estimate, and the registry does not provide a confidence interval for the contrast. Readers therefore cannot assess the range of contrasts compatible with the model from the primary result alone. The means and standard errors offer useful descriptive information, but they do not replace an explicit estimate and interval.

Finally, the broader research summary includes several aims, while the posted primary result addresses maximal knee extensor power. The registry lists many outcomes and analyses but does not explain the multiplicity plan or analysis populations. Keeping the primary measure separate from the study’s wider questions helps prevent a narrow statistical finding from being treated as evidence about outcomes that were not reported.

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 provides limited detail for independently evaluating the primary analysis. It reports a two-sided t-test, but does not identify whether it was paired, describe the use of treatment sequence or period, or report a model that accounts for the crossover design. The test statistic, degrees of freedom, treatment-effect estimate, and confidence interval are not reported in the registry record.

The primary endpoint was assessed in 9 participants, while overall enrollment is listed as 17. The record does not explain this difference, identify the participants included in each treatment condition, or report how incomplete observations were handled. It also does not report participant-level values, standard deviations, or the number with complete measurements under both conditions.

The registry describes a broader set of study aims and lists 27 outcome measures and 22 analyses, but does not specify a multiplicity strategy or make clear which analyses were prespecified. The result for the listed secondary outcome, VO2peak, is not included in the registry record for this analysis. No trial-specific sample-size justification is reported, and numerical planning illustrations are not included.

Other design details that could inform interpretation, including the treatment sequence, treatment-period duration, and washout between conditions, are not reported in the registry record. The adverse-event entries also lack a stated observation timeframe and detailed collection methods. These limitations do not change the reported means or test result, but they restrict conclusions about precision, robustness, missing data, and the wider set of study questions.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Dietary Nitrate for Heart Failure — NCT01682356.
• Registry record last updated 2024-12-04; status last verified 2024-11.
• Results first posted 2024-12-04.
• 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

NCT01682356, titled Dietary Nitrate for Heart Failure, is listed as a completed Phase 1 and Phase 2 randomized, double-masked crossover study sponsored by Washington University School of Medicine. Enrollment is 17. The registry lists heart failure and pulmonary hypertension among the conditions and gives a start date of 2012-01 and primary completion date of 2023-07-01.

The primary endpoint is maximal knee extensor power in W/kg, measured using isokinetic dynamometry 2-3 h after an acute dose. The registry reports means of 4.2 for placebo and 4.74 for nitrate, with standard errors of 0.33 and 0.41, respectively; 9 participants were assessed. The sponsor-reported two-sided t-test has p = 0.015.

The record does not report a confidence interval, a contrast estimate, or enough detail to establish how the crossover structure was incorporated into the test. It lists 27 outcome measures and 22 analyses, without reporting a multiplicity plan. Adverse-event entries list 0 serious events, 0 other events, and 0 deaths for each condition, among 17 at risk per condition.