Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability (NCT01059994), a randomized na study. The primary outcome is Change in Muscle Fatigue After 1 Week of Placebo or Sildenafil.

2. Clinical Question

The broader research question concerned skeletal muscle nitric oxide production, muscle strength, physical function, fatigue, and fatigability. The brief summary also describes testing a method intended to determine vascular and skeletal muscle nitric oxide production. The endpoint results listed in the registry focus on repetitions, rather than a reported nitric oxide measurement. The clinical question that can be assessed from these results is therefore narrower than the full mechanistic aim: what happened to the reported repetition measure in the treatment and placebo groups, and how much inferential support does the registry provide for a treatment comparison?

3. Trial Design

The registry describes a randomized, triple-masked, parallel trial with enrollment of 12. Its phase is listed as not applicable. The study status is completed. The record lists The University of Texas Medical Branch, Galveston, as sponsor and describes the project as a pilot study funded by the National Institutes of Health.

The arm descriptions distinguish younger subjects ages 20-35 from older subjects ages 60-80. Within each age category, subjects received placebo sildenafil or sildenafil daily for 1 week. Sildenafil is specified as 25 mg/day in the arm descriptions. The primary outcome was assessed from baseline to 1 week. These features produce four reported groups: younger placebo, younger sildenafil, older placebo, and older sildenafil.

For the primary outcome, the registry reports group sizes of 3, 2, 3, and 3, respectively. The record does not explain how these outcome group counts relate to the stated enrollment of 12. Nor does it report the randomization method, allocation ratio, concealment procedures, or the specific roles masked by triple masking. These design details should not be inferred from the trial labels alone.

The stated research purpose was to investigate potential effects of skeletal muscle nitric oxide production on strength and physical function in older individuals, and to assess whether sildenafil might alter fatigue and fatigability. The primary endpoint reported is a repetition-based measure. A secondary outcome is listed as protein synthesis rate after 1 week of sildenafil or placebo. Detailed results for that secondary outcome are not reported in the registry record. The brief summary gives the scientific aims, but does not supply a detailed protocol or statistical analysis plan.

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: Participants who failed screening, did not otherwise meet inclusion criteria, or decided not to participate were excluded before being assigned to intervention groups.

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 Muscle Fatigue After 1 Week of Placebo or Sildenafil, measured over baseline to 1 week.

The primary endpoint is titled change in muscle fatigue after 1 week of placebo or sildenafil. It uses the percent change in successful repetitions from baseline to 1 week. Participants performed maximum-effort isokinetic knee extensions until force production reached 50% of maximum voluntary contraction; the recorded measure was the number of successful repetitions completed before that threshold.

This task provides an operational measure of performance during repeated effort. In general, a repetition-based endpoint can represent the ability to continue producing force under a defined testing condition. It is not a direct measure of nitric oxide production, and the posted endpoint description does not equate the repetition measure with every aspect of fatigue, fatigability, strength, or everyday physical function.

The registry presents the endpoint as a mean with standard deviation. The reported group means are 107 for younger placebo, 115 for younger sildenafil, 54 for older placebo, and 158 for older sildenafil. The corresponding reported group sizes are 3, 2, 3, and 3, and the standard deviations are 5, 10, 31, and 27. These summaries describe the groups; they do not by themselves establish that a difference between treatments is statistically reliable. Interpretation also depends on the comparison being tested, uncertainty around the estimates, and the limited number of observations in each group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help distinguish what the posted results say from what they cannot establish. These are general explanations of the methods, followed by the details that the registry reports for this trial.

What does a mean and standard deviation describe?

For a continuous outcome, a mean gives the arithmetic average of the observations in a group. A standard deviation describes how dispersed the observed values are around that mean. They answer different questions: the mean describes the group’s central value, while the standard deviation describes variability among its observations. Neither measure alone shows the uncertainty in a comparison between groups.

For this endpoint, the registry reports means and standard deviations for four groups. The outcome is the percent change in successful repetitions from baseline to 1 week. The group sizes are small, so a few observations may have substantial influence on the mean and standard deviation. In general, summaries based on small groups may be unstable; they should be read as descriptions of the observed participants rather than precise estimates for a wider population.

What does the reported t-test assess?

The registry identifies a two-sided t-test for the comparison between younger placebo and younger sildenafil, with p = 0.02. In general, a two-sided test evaluates evidence for a difference in either direction, rather than limiting the alternative to an increase or a decrease. A t-test compares group means relative to the variability and sample sizes, under assumptions associated with that test. The registry does not report enough detail to assess all assumptions or to determine whether any alternative analysis was planned.

A p-value is calculated under a null hypothesis and the test’s assumptions. A value such as p = 0.02 is not the probability that the null hypothesis is true, nor does it quantify the probability that a result is due to chance in an unrestricted sense. It does not measure clinical importance. The result is specific to the comparison and outcome tested. The record reports no equivalent sponsor test for the older groups.

Why do confidence intervals matter?

In general, a confidence interval gives a range of effect estimates compatible with the data under a stated method, conveying precision as well as direction. A p-value alone does not show the estimated effect’s range or how uncertain that estimate is. The registry record does not report a confidence interval for the sponsor’s younger-group test. The available means and standard deviations are not a substitute for that interval, and no interval should be inferred from them in the explanatory interpretation.

The small number of observations is especially relevant to precision. Small groups tend to provide limited information about the range of plausible effects, and any test result can be sensitive to individual values. The standard deviations also indicate different levels of observed spread across the four groups, but the summaries do not reveal the shapes of the underlying distributions. Individual-level results and diagnostic information are not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion occurs when variability is greater than a model assumes. If a method understates variability, its uncertainty estimates can be too narrow and its tests can appear more decisive than warranted. This is a general statistical concern, not a finding about this trial: the endpoint is continuous, and the registry does not report a model-based analysis or evidence of over-dispersion. The relevant caution is that the record provides only small-group summaries and limited inferential detail.

How should recalculated results be understood?

In general, a recalculation from posted summary statistics is an unadjusted analysis, distinct from the sponsor’s analysis based on the trial data and its specified methods. It can help readers understand the numerical summaries, but it cannot reproduce unreported features of the original analysis, such as adjustments or data-handling choices. Any recalculated result should therefore be read as a check based on the available summaries, not as a replacement for the sponsor’s analysis. The record does not flag a discrepancy between the sponsor’s result and the recalculation.

What do sample-size illustrations mean?

In general, sample-size planning illustrations describe how many participants might be needed under specified assumptions about the effect to detect, significance level, allocation, and statistical approximation. They are planning scenarios, not evidence about what the trial observed and not observed power. The record’s planning assumptions refer to an effect expressed as a fraction of the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions do not establish the trial’s actual design rationale or show that the trial was planned using that approach. The protocol’s sample-size justification is not reported in the registry record.

The registry reports only one sponsor test for the primary endpoint in the listed analyses and does not describe the complete statistical plan. Accordingly, interpretation should keep the outcome summaries, the one reported test, any unadjusted recalculation, and any planning illustration conceptually separate.

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 Sildenafil Young", "Sildenafil Young", "Placebo Sildenafil Older", "Sildenafil Older")
n   <- c(3, 2, 3, 3)
m   <- c(107, 115, 54, 158)
sp  <- c(5, 10, 31, 27)
sd  <- sp      # posted standard deviations
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 Sildenafil Young  3  107.000  5.000  94.579  119.421
CARM  Sildenafil Young  2  115.000  10.000  25.154  204.846
CARM  Placebo Sildenafil Older  3  54.000  31.000  -23.008  131.008
CARM  Sildenafil Older  3  158.000  27.000  90.928  225.072

11. Analyses Reported by the Sponsor

The sponsor-reported analysis is a two-sided t-test comparing younger subjects assigned to placebo sildenafil with younger subjects assigned to sildenafil. The reported p-value is 0.02. It is the sponsor’s own inferential result for that comparison. The registry does not report a sponsor test for the older placebo and sildenafil groups, so the younger-group p-value should not be extended to them.

A recalculated contrast, when based on posted summary statistics, is a simple unadjusted re-calculation. It can provide a separate check on the reported comparison, but it may not reproduce analysis choices made using the trial’s underlying data. No discrepancy is flagged between the sponsor’s result and the recalculation. The registry does not report a confidence interval for the sponsor’s comparison, and the p-value does not supply one.

The group summaries and the sponsor’s test serve different purposes. Means and standard deviations describe observed groups, whereas the test evaluates a particular comparison under its statistical assumptions. The p = 0.02 result is limited to the younger groups and the primary repetition endpoint. It does not constitute a test of the older groups, an age interaction, the secondary protein synthesis outcome, or the broader nitric oxide mechanism. Details of the sponsor’s full statistical plan, including any additional analyses, are not reported in the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary endpoint as change in muscle fatigue after 1 week and lists protein synthesis rate after 1 week of sildenafil or placebo as a secondary outcome. It reports 2 outcome measures, but detailed results for the secondary outcome are not reported in the registry record. The record does not describe a prespecified hierarchy among outcomes or explain how multiple statistical tests were handled.

In general, when researchers examine multiple outcomes, groups, time points, or comparisons, the chance of obtaining at least one apparently notable result can increase. Statistical approaches may address this multiplicity, but whether an adjustment is appropriate depends on the study’s plan and aims. No multiplicity adjustment or strategy is reported in the registry record. The reported p = 0.02 should therefore be interpreted as the result for its named comparison, without assuming that it was or was not adjusted for other analyses.

The record also does not report how missing primary-outcome observations were handled, whether all randomized participants were included in the endpoint analysis, or which analysis population was used. It does not describe withdrawals, exclusions, protocol deviations, or an intention-to-treat analysis. Those details matter because analysis populations and missing-data methods can affect what a group comparison represents. The registry reports primary-outcome group sizes of 3, 2, 3, and 3, while the stated enrollment is 12; the record does not explain their relationship.

For safety, the older sildenafil group has 4 participants listed as at risk in the adverse-event information, whereas its primary-outcome group size is 3. The record does not explain this difference. The outcome analysis and adverse-event reporting should therefore be read as separate records with their own listed counts, rather than assumed to use identical populations.

The protocol, detailed analysis plan, missing-data approach, and analysis-population definitions are not reported in the registry record. Without those details, it is not possible to determine whether the reported test was the sole planned test, how all intended analyses were prioritized, or how incomplete data might have affected results.

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 serious adverse events, other adverse events, and deaths by group. For younger placebo, the listed counts are 0 serious adverse events, 0 other adverse events, and 0 deaths among 3 at risk. For younger sildenafil, they are 0, 0, and 0 among 2 at risk. For older placebo, they are 0, 0, and 0 among 3 at risk. For older sildenafil, they are 0, 0, and 0 among 4 at risk.

These are counts recorded in the registry, not proof that no adverse events could occur. The group sizes are small, and a short treatment period of 1 week offers limited information about less common events or effects beyond that period. The adverse-event record lists no serious-event terms. It does not provide further detail about the method of event collection, event definitions, or the timing of surveillance.

The older sildenafil group’s adverse-event count uses 4 participants at risk, while the primary-outcome group lists 3. The registry does not explain the difference. Safety counts should therefore be interpreted using their own reported at-risk figures, not assumed to correspond exactly to the primary endpoint analysis population. The data describe what the registry records for these groups and do not establish a general safety profile.

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

The results show the reported repetition-based endpoint for four small groups, together with a sponsor-reported test comparing the younger placebo and sildenafil groups. The younger-group means were 107 and 115, respectively, and the reported two-sided test had p = 0.02. The older-group means were 54 with placebo and 158 with sildenafil, but the registry does not report a sponsor test for that comparison. These observations are descriptive evidence from the listed participants, not a basis for a broad conclusion about treatment effects.

The result does not determine whether sildenafil changes fatigue or fatigability in older individuals. The primary test reported is for younger participants, and no formal comparison of treatment effects across age categories is reported. Nor does the endpoint directly establish a change in nitric oxide production. Although the study’s aims concern nitric oxide and physical function, the reported primary outcome is successful repetitions during a laboratory knee-extension task.

In general, statistical evidence and clinical importance are distinct. A p-value does not state the size of an effect or its practical meaning. The registry does not report a confidence interval for the sponsor test, and the small group sizes limit the precision that can be inferred from the summaries. The secondary outcome is listed, but its numerical results are not reported in the registry record.

The findings also do not establish how results would apply outside the study’s age categories, under different treatment durations, or for other measures of daily function. The registry describes a 1-week intervention and a pilot study. The data can inform a careful reading of the recorded groups and the reported test, but do not answer every question raised by the study’s broader scientific aims.

15. Why This Trial Matters Statistically

This trial illustrates why the comparison attached to a statistical result matters as much as the result itself. The registry’s p = 0.02 applies to the younger placebo and sildenafil groups. It does not answer the same question for older participants, even though older participants were included and have reported endpoint summaries. Keeping those comparisons separate prevents a result in one age category from being treated as evidence about all groups.

The record also shows the difference between descriptive and inferential information. Means and standard deviations summarize observed outcomes; a test addresses a specified hypothesis; a confidence interval would describe uncertainty around an estimate. The registry reports group summaries and one sponsor test, but no confidence interval for that comparison. With only 2 or 3 primary-outcome observations per group, the limits of precision deserve particular attention.

A further statistical lesson is that a mechanistic research aim and a clinical-performance endpoint are not interchangeable. The stated project concerns skeletal muscle nitric oxide production and function, while the posted primary result measures successful repetitions. A result for repetitions cannot, by itself, quantify a nitric oxide response. The listed secondary outcome concerns protein synthesis, but its detailed results are not reported in the registry record.

Finally, a completed pilot trial can be informative about how an endpoint and comparison are reported without resolving every scientific question. Missing details about analysis populations, multiplicity, and sample-size justification constrain interpretation. Separating those unknowns from the posted summaries helps readers understand both the statistical signal and the boundaries of what the registry record can support.

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.

This trial’s primary-outcome groups are small: the registry reports 3 participants for younger placebo, 2 for younger sildenafil, 3 for older placebo, and 3 for older sildenafil. Such group sizes provide limited information about variability and make mean estimates potentially sensitive to individual observations. The registry provides no confidence interval for the sponsor-reported younger-group comparison.

The primary endpoint is a repetition-based laboratory task, measured from baseline to 1 week. It represents performance under the described knee-extension test and is not a direct measure of every aspect of fatigue, physical function, or nitric oxide production. The record does not report individual outcome values or detailed baseline results that would allow readers to assess how the change summaries were formed or whether particular observations were influential.

The only sponsor-reported test identified is for the younger groups. The older-group summaries have no corresponding sponsor-reported test in the registry record. A formal comparison of treatment effects between age categories is also not reported. As a result, the record cannot establish whether the treatment contrast differs by age.

Other limitations arise from missing reporting details. The registry does not describe the sample-size justification, analysis populations, missing-data handling, multiplicity strategy, randomization procedures, or the operational details of triple masking. It lists a secondary protein synthesis outcome but does not report its results. The relationship between stated enrollment and outcome group counts is not explained; nor is the difference between the older sildenafil primary-outcome count and its adverse-event at-risk count.

The intervention lasted 1 week, and the study is described as a pilot. The registry record therefore offers limited information about outcomes beyond that period. These limitations do not negate the recorded summaries or the reported test, but they constrain how broadly and precisely those results can be interpreted.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability — NCT01059994.
• Registry record last updated 2019-02-11; status last verified 2018-11.
• Results first posted 2015-12-23.
• 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

The registry describes a completed randomized, triple-masked, parallel pilot study of sildenafil and placebo in younger subjects ages 20-35 and older subjects ages 60-80. The intervention period was 1 week, with sildenafil specified as 25 mg/day. Enrollment is listed as 12.

The primary outcome was percent change in successful knee-extension repetitions from baseline to 1 week. The record reports means, standard deviations, and group sizes for four age-and-treatment groups. A two-sided t-test with p = 0.02 is reported for the younger placebo versus younger sildenafil comparison. No sponsor-reported test for the older groups is reported in the registry record.

Protein synthesis rate is listed as a secondary outcome, but its detailed results are not reported. The adverse-event record lists zero serious adverse events, zero other adverse events, and zero deaths in each group, using the at-risk counts recorded for safety. Missing analysis details and small group sizes limit precision and broader interpretation.