This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF (NCT02256345), a randomized phase 2 study. The primary outcome is Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02256345 |
| Phase | Phase 2 |
| Condition | Heart Failure, Diastolic Heart Failure |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Single |
| Enrollment | 12 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Pennsylvania |
| Results posted | Yes |
2. Clinical Question
Population
People with heart failure, including diastolic heart failure, were the population of interest. The registry record describes a completed phase 2 study with an enrollment of 12. It does not provide a more detailed description of participant characteristics or the primary-outcome analysis population.
Intervention
The intervention was KNO3, an inorganic nitrate. The planned regimen began at 6 mmol twice daily for the first week and increased to 6 mmol three times daily for the second week if well tolerated.
Comparator
The comparator was KCl, described in the registry record as a placebo. Its planned schedule was 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated.
Primary question
The primary outcome concerned change in peak oxygen uptake, or peak VO2, from baseline through up to one week of administration for each dose. The broader study goals also included characterizing KNO3 pharmacokinetics and examining whether nitrate supplementation was associated with a dose-response pattern in exercise capacity and physiological adaptations to exercise.
The question is therefore about both dose and measurement over time: how peak VO2 changed during the planned treatment periods, and whether those changes varied by dose. The registry record identifies baseline, the end of week 1, and the end of week 2 as measurement time points. It does not report numerical peak VO2 changes, confidence intervals, or a statistical comparison between KNO3 and KCl. The record also does not specify a single contrast that would represent the overall dose-response question. Consequently, the stated aims can be described, but the magnitude and precision of any treatment-related difference cannot be assessed from the recorded primary-outcome information.
3. Trial Design
The registry classifies this as a randomized, single-masked, parallel phase 2 study. The sponsor is the University of Pennsylvania. The study status is completed, and the enrollment is 12. The recorded start is 2015-01, and the primary completion is 2016-06. The record does not identify who was masked, so the masking label should not be interpreted more specifically.
Participants were assigned to KNO3 or KCl. The record describes KCl as the placebo comparator. Both arms followed the same planned escalation schedule: 6 mmol twice daily during the first week, with an increase to 6 mmol three times daily during the second week if well tolerated. This matching schedule is relevant to interpretation because it indicates that the planned dosing frequency and escalation criteria were described similarly for the two arms. The record does not report adherence, actual dose received, or how many participants progressed to the second-week schedule.
The primary outcome was a continuous measure: change in peak oxygen uptake, in L/min. Peak VO2 was defined as the average value obtained during the last 30 seconds of exercise. The stated timeframe included baseline, the end of week 1, and the end of week 2. The primary outcome title refers to change from baseline up to one week of administration for each dose, while the timeframe also names the end of week 2. The registry does not explain how these descriptions map to the specific comparisons or analyses.
Other listed outcomes were change in vasodilatory reserve for each dose, change in mitochondrial oxidative capacity for each dose, and change in aortic augmentation index. The record lists four outcome measures overall but does not provide numerical results for them. It also does not report the allocation ratio, the sequence-generation method, concealment procedures, or the detailed analysis plan. Those aspects should not be inferred from the randomized, single-masked, parallel 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
| Stage | Randomized to KNO3 | Randomized to KCl |
|---|---|---|
| STARTED | 9 | 3 |
| COMPLETED | 9 | 3 |
| NOT COMPLETED | 0 | 0 |
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.
| Characteristic | Unit | Randomized to KNO3 | Randomized to KCl | Total |
|---|---|---|---|---|
| Participants analysed | 9 | 3 | 12 | |
| Age, Continuous | years | 62.4 (SD 5.5) | 62.7 (SD 8.0) | 62.5 (SD 5.8) |
| Sex: Female, Male: Female | Participants | 6 | 2 | 8 |
| Sex: Female, Male: Male | Participants | 3 | 1 | 4 |
| Race/Ethnicity, Customized: Race, n (%) – White | Participants | 5 | 3 | 8 |
| Race/Ethnicity, Customized: Race, n (%) – Black | Participants | 3 | 0 | 3 |
| Race/Ethnicity, Customized: Race, n (%) – Pacific Islander | Participants | 1 | 0 | 1 |
| New York Heart Association Heart failure classification (NYHA Class) n (%): Class II | Participants | 8 | 2 | 10 |
| New York Heart Association Heart failure classification (NYHA Class) n (%): Class III | Participants | 1 | 1 | 2 |
| Body Mass Index, kg/m^2, mean (SD) | kg/m^2 | 33.4 (SD 6.3) | 37.4 (SD 9.9) | 34.4 (SD 7.0) |
| Number of Obese Participants, n(%) | Participants | 5 | 3 | 8 |
| Number of Hypertensive Participants, n(%) | Participants | 9 | 3 | 12 |
| Number of Participants with Hyperlipidemia, n (%) | Participants | 7 | 3 | 10 |
| Number of Participants with Coronary Artery Disease, n (%) | Participants | 3 | 1 | 4 |
| Number of Participants with History of atrial fibrillation, n (%) | Participants | 0 | 1 | 1 |
| Number of Participants with Diabetes Mellitus, n (%) | Participants | 5 | 2 | 7 |
| Number of Participants with Obstructive sleep apnea, n (%) | Participants | 3 | 3 | 6 |
| Number of Participants with Current Continuous Positive Airway Pressure (CPAP) use, n (%) | Participants | 2 | 3 | 5 |
| Number of Participants with Obstructive lung disease, n (%) | Participants | 2 | 1 | 3 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose, measured over Baseline, end of week 1, end of week 2.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | L/min |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change in peak oxygen uptake (VO2), measured in L/min. Peak VO2 is defined in the registry record as the average value obtained during the last 30 seconds of exercise. Measurements were specified at baseline, the end of week 1, and the end of week 2. The outcome description refers to change from baseline for each dose, but does not specify a single summary contrast or provide numerical changes.
As a general statistical and physiological concept, peak oxygen uptake is used as an indicator of exercise capacity because it records oxygen uptake near the end of an exercise test. A change score compares a follow-up measurement with a baseline measurement, which can describe how the measured value shifts during the study period. The meaning of a change depends on the measurement procedures, the time point, and how the analysis handles repeated observations and differences between participants.
Because this is a continuous outcome, results might ordinarily be reported as a mean change with a measure of uncertainty. The registry identifies the mean as the parameter and a 95% confidence interval as the dispersion measure. However, no endpoint estimate or confidence interval is reported in the registry record. The endpoint's definition and intended time points can therefore be described, but its observed direction, magnitude, and precision cannot be determined from the available record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record establishes the trial's principal outcome question but does not provide the numerical primary-outcome results needed to answer it. It identifies change in peak VO2, measured in L/min, as the primary endpoint and states that the outcome was considered across doses and time points. It supplies no mean changes, confidence interval limits, or test statistics for peak VO2. No treatment effect should therefore be inferred from the study aims or endpoint definition alone.
The record identifies a randomized comparison of KNO3 with KCl and describes the latter as a placebo comparator. Randomization is intended, in general, to support a fair comparison by distributing participant characteristics without deliberate selection into one arm. That design feature does not by itself establish that the groups were comparable in this particular small study, nor does it replace reporting of outcome estimates and uncertainty. The registry enrollment is 12, and the adverse-event risk counts are 9 for KNO3 and 3 for KCl; these safety counts should not be assumed to define the primary-outcome analysis population.
A confidence interval, in general, expresses statistical uncertainty around an estimate under the assumptions of the analysis. Its width can help readers judge how precisely an effect has been estimated. Here, the record names a 95% confidence interval as the dispersion measure for the mean outcome, but does not include its limits. There is consequently no basis in the registry record to assess whether the estimate was precise or compatible with a range of effects.
The study's two stated goals include characterizing population-specific pharmacokinetics and identifying a possible dose-response effect on exercise capacity and physiological adaptations. The primary endpoint is relevant to the exercise-capacity goal, while the additional outcomes concern vasodilatory reserve, mitochondrial oxidative capacity, and aortic augmentation index. The registry gives no numerical results for these outcomes and no detailed pharmacokinetic findings. It is not possible to assess the size or consistency of any pattern across dose, time, or outcome.
The appropriate reading is therefore descriptive and limited: the registry records a completed randomized trial with a defined endpoint and planned dosing schedules, but its posted primary-outcome information does not establish the observed effect or its precision. This absence of reported results is not evidence that there was no change or no difference. It means the result cannot be evaluated from the registry record.
9. Statistical Methods Explained
What does the mean describe?
The primary outcome is continuous, and the registry identifies the mean as its summary parameter. In general, a mean describes the central value of measurements in a group. A mean change would describe the average difference between follow-up and baseline measurements among the participants included in the analysis. It does not show how much individual participants varied, and it can be affected by extreme observations. Interpretation therefore depends on knowing which participants were analyzed and how incomplete measurements were handled.
The endpoint is peak VO2 in L/min, defined as the average oxygen uptake during the last 30 seconds of exercise. The record names baseline, end of week 1, and end of week 2 as time points. Repeated measurements on the same participant are related observations rather than independent measurements. In general, an analysis of repeated measurements needs to account for that relationship if it combines observations across time. The registry record does not describe the model or method used to handle repeated measurements.
How should a confidence interval be read?
The record specifies a 95% confidence interval as the dispersion measure for the primary outcome. In general, a confidence interval gives a range of values compatible with an estimate under the statistical model and its assumptions. It is used to communicate uncertainty, not to certify that a finding is true or to measure clinical importance by itself. Its interpretation depends on the analysis and on the quality and completeness of the data.
No confidence interval limits or mean estimates are reported for the primary endpoint. As a result, the stated confidence level does not allow readers to judge the precision of the peak VO2 estimate. A confidence interval cannot be reconstructed from the endpoint definition, enrollment, or adverse-event counts, and no reconstruction is warranted from those details.
What does dose-response mean statistically?
In general, a dose-response question asks whether the outcome changes systematically across different dose levels. Answering it requires clear information about the dose levels actually received, the outcome at each relevant time, and the statistical contrast or trend being assessed. The protocol description records escalation from 6 mmol twice daily to 6 mmol three times daily if well tolerated. It does not report how many participants received each schedule or define a statistical test for a dose-response pattern.
The primary outcome wording refers to change for each dose, while the timeframe includes three measurement points. These details describe the intended scope of measurement but do not establish how dose and time were combined analytically. The analysis model, any adjustment for baseline values, and any handling of participants who did not tolerate escalation are not reported in the registry record.
What can the planning assumptions tell us?
The record describes a sample-size planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. This description is a planning framework, not evidence about the trial's original design or its achieved ability to detect an effect. The record does not give the planning illustration's participant counts or identify a trial-specific sample-size justification.
In general, such planning calculations illustrate how sample size can depend on the assumed effect and statistical assumptions. When planning uses an effect observed in the same study, the resulting illustration should not be treated as observed power or as proof that the trial was adequately sized. The registry record does not report a separate power calculation for the actual study design, and the numerical primary-outcome estimate needed to evaluate the illustration is not reported.
Why do distributional assumptions matter?
A normal approximation is named for the planning illustration, but the record does not state the distributional assumptions or model used for the primary endpoint analysis. In general, statistical methods rely on assumptions about how observations vary and how measurements relate to one another. With continuous outcomes, distribution shape and unusual values can affect the mean and the reliability of model-based uncertainty estimates. With repeated measurements, within-participant correlation also matters. The record does not provide diagnostic checks or enough detail to assess these issues.
The registry identifies no analyses in its analysis listing. That does not justify inferring which tests, models, or adjustments were used in practice. The absence of numerical endpoint results also means that no recalculation from posted summary statistics is possible. Statistical conclusions should remain limited to the outcomes and methods explicitly documented in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The trial includes more than one outcome and more than one measurement time. Alongside peak VO2, the registry lists changes in vasodilatory reserve, mitochondrial oxidative capacity, and aortic augmentation index. The primary outcome description refers to each dose, and the timeframe names baseline, the end of week 1, and the end of week 2. When several outcomes, doses, or time points are examined, the chance of at least one apparently notable result can increase. In general, a prespecified strategy for handling multiple comparisons can help clarify which findings are confirmatory and how uncertainty should be interpreted.
A multiplicity strategy is not reported in the registry record. The record does not specify a hierarchy among the outcomes, a correction method, or which dose and time contrasts were intended as primary comparisons. The primary outcome title and timeframe also do not define one unambiguous contrast. Therefore, readers cannot determine how the study addressed the possibility of multiple testing.
The registry record does not report how missing outcome measurements were handled, whether all randomized participants were included in the primary analysis, or what analysis population was used. It does not describe exclusions, withdrawals, or the handling of measurements after a participant did not tolerate escalation. These details matter because incomplete measurements or exclusions can affect both the estimated mean change and its uncertainty.
In general, a complete account of missing-data methods identifies what was missing, the assumptions made about missingness, and the method used to analyze incomplete records. None of these methods is described. The record also does not report an interim-analysis plan or an analysis-population definition. These absences should be treated as unreported information, not as evidence that no missing data, interim analyses, or exclusions occurred.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Randomized to KNO3 | 0 | 9 | 0.0% |
| Randomized to KCl | 0 | 3 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Randomized to KNO3 | 0 of 9 |
| Randomized to KCl | 0 of 3 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Randomized to KNO3 | 5 of 9 |
| Randomized to KCl | 1 of 3 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Randomized to KNO3 | Randomized to KCl |
|---|---|---|---|
| Any side effect | General disorders | 4 of 9 | 1 of 3 |
| GI symptoms | Gastrointestinal disorders | 3 of 9 | 1 of 3 |
| Headache | Nervous system disorders | 2 of 9 | 0 of 3 |
| Palpitations | Cardiac disorders | 1 of 9 | 0 of 3 |
| Mild lower extremity edema | Cardiac disorders | 0 of 9 | 1 of 3 |
| Tooth infection | Infections and infestations | 1 of 9 | 0 of 3 |
| Fatigue | General disorders | 1 of 9 | 0 of 3 |
The registry's adverse-event counts list no serious adverse events and no deaths in either randomized group. For KNO3, the number at risk for serious adverse events was 9, with 0 affected; the number at risk for other adverse events was 9, with 5 affected. For KCl, the corresponding serious-event count was 0 among 3 at risk, and the other-adverse-event count was 1 among 3 at risk. These are the recorded counts, not estimates of comparative risk.
In general, an at-risk count identifies the group denominator used for the corresponding event category, while an affected count identifies participants recorded with an event. Serious and other adverse events are separate categories in the registry record. The event counts alone do not describe event type, severity within the nonserious category, timing, duration, or attribution to study treatment. No top serious-event terms are listed.
The risk counts differ between the two groups, and the registry enrollment is 12. The record does not explain the difference between these counts and total enrollment, or whether the same participants were included in each adverse-event category. These figures should not be used to infer a treatment effect or to make a broad safety comparison. The study is small, and the adverse-event information is limited to the recorded counts; fuller safety interpretation would require event details and a clear account of exposure and follow-up.
12. What the Result Does, and Does Not, Mean
This trial's registry record describes a randomized phase 2 comparison of KNO3 with KCl in a study concerning HFpEF. It defines peak VO2 change as the primary outcome and records a mean with a 95% confidence interval as the intended summary. It also describes two weeks of planned dose escalation, contingent on tolerability, and lists additional physiological outcomes. These details identify what the study set out to examine.
They do not establish what happened to peak VO2. Numerical outcome estimates, confidence interval limits, and statistical comparisons are not reported in the registry record. The record therefore cannot show the direction, magnitude, or precision of a difference between groups or across dose levels. The stated goal of finding a dose-response effect is not itself evidence that such a pattern was observed.
The missing numerical findings also prevent readers from judging how results varied over time, whether the additional outcomes supported a similar interpretation, or how the pharmacokinetic goal was addressed. The study's completed status is not a substitute for outcome results. Likewise, an adverse-event count of zero serious events in the listed groups does not establish that there was no risk, particularly without event-level detail and fuller exposure information.
In general, a trial result is interpreted by considering the estimated effect, its uncertainty, the analysis population, the design, and the limitations of measurement and follow-up. Here, several of those elements are not reported. The appropriate conclusion is not that KNO3 changed or did not change exercise capacity, but that the registry record does not provide the primary-outcome results needed to assess that question. The record supports a description of the design and intended measurements, not a conclusion about treatment efficacy or a definitive safety comparison.
13. Why This Trial Matters Statistically
This study raises several statistical questions that are important in small randomized trials. It combined an outcome measured repeatedly over time with a dose-escalation plan and a stated interest in dose response. Those features make it important to distinguish the treatment comparison at a particular time from a pattern across doses and time points. A clearly defined primary contrast and analysis plan would help readers understand which estimate answers the main question.
The registry identifies the primary outcome as a continuous measure and names a mean and 95% confidence interval as its summary. That is a useful framework for reporting both the estimated average change and its uncertainty. However, the numerical estimate and interval are not reported in the registry record. Without them, it is not possible to assess whether the study produced a precise estimate, whether uncertainty was substantial, or how the findings related to the planned dose-response question.
Small studies also highlight the difference between a planning calculation and evidence from an observed result. The record describes a planning illustration based on an observed effect and specified statistical assumptions, but does not provide the illustration's participant counts or a trial-specific sample-size justification. Such an illustration should not be read as observed power. More generally, planning calculations depend on their assumptions and do not replace transparent reporting of the actual estimate and its uncertainty.
Finally, the record illustrates why a completed status and a defined outcome do not, by themselves, make a study's findings interpretable. Reporting the analysis population, missing-data methods, handling of multiple outcomes and time points, and numerical estimates would allow a more complete statistical assessment. These considerations apply broadly to clinical research; in this trial, the relevant methods and primary results are not reported in the registry record.
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 trial-specific limitation for interpreting the primary question is that no numerical peak VO2 results are reported in the registry record. The mean change and its 95% confidence interval are not given, and no between-group comparison or dose-response estimate is available. The primary outcome title refers to change for each dose, while the stated timeframe includes baseline and the ends of both weeks; the record does not clarify the exact comparisons represented by these descriptions.
The enrollment is 12, and the adverse-event counts list 9 at risk for KNO3 and 3 for KCl. The record does not state the primary analysis population or explain how it relates to these counts. It also does not report participant characteristics, adherence, actual dose received, withdrawals, missing outcome measurements, or reasons for any unavailable measurements. These omissions limit assessment of who contributed to each outcome and how representative the analyzed group might have been.
The record classifies the study as randomized, single-masked, and parallel but does not describe sequence generation, allocation concealment, or who was masked. It does not specify the statistical model, treatment of repeated observations, baseline adjustment, multiplicity strategy, or analysis populations. The sample-size planning assumptions are described, but the registry does not report a trial-specific justification or the numerical planning outputs. No interim-analysis information is reported.
These limitations concern what can be assessed from the registry record; they do not demonstrate that a particular method was or was not used. In particular, unreported methods should not be guessed, and missing endpoint results should not be interpreted as a null finding. The listed adverse-event counts are also too limited to characterize event types, timing, or treatment attribution.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF — NCT02256345.
- Registry record last updated 2017-10-03; status last verified 2017-08.
- Results first posted 2017-10-03.
- 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.
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18. Record Summary
The registry describes a completed randomized, single-masked, parallel phase 2 study sponsored by the University of Pennsylvania, with enrollment of 12. It compared KNO3 with KCl, described as a placebo comparator. Both planned regimens began at 6 mmol twice daily for the first week and increased to 6 mmol three times daily for the second week if well tolerated.
The primary outcome was change in peak VO2 in L/min, defined as the average value during the last 30 seconds of exercise, with measurements specified at baseline and the ends of weeks 1 and 2. Additional outcomes concerned vasodilatory reserve, mitochondrial oxidative capacity, and aortic augmentation index. The record lists no serious adverse events or deaths in either group, alongside the reported other-adverse-event counts.
Numerical primary-outcome estimates, confidence intervals, and detailed statistical methods are not reported in the registry record. Thus, the study aims and design can be described, but the registry information does not support an assessment of the primary treatment effect or its precision.