Free Fatty Acids-Induced Hypertension in Obese Subjects (Aim #2): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Free Fatty Acids-Induced Hypertension in Obese Subjects (Aim #2) (NCT02406586), a randomized na study. The primary outcome is Change in Systolic Blood Pressure..

2. Clinical Question

The study’s stated purpose was to investigate whether salsalate or carvedilol would protect against several effects associated with free fatty acid exposure in obese normotensive subjects. Those effects included hypertension, insulin resistance, endothelial dysfunction, inflammation and oxidative stress, and autonomic dysfunction. The primary outcome reported for this analysis is narrower: change in systolic blood pressure from immediately before Intralipid dosing to four hours into the infusion.

The registry describes randomized, double-masked, parallel groups. The posted primary results give a mean change for each of the salsalate, carvedilol, and placebo arms, along with treatment-versus-placebo comparisons. These results address the blood-pressure measure at the stated assessment, not every biological outcome in the study’s purpose. The registry record does not report primary results for the other listed outcomes in the information available for this analysis.

3. Trial Design

The registry record identifies this as a randomized, double-masked, parallel-group study sponsored by Emory University. Its status is completed, and its phase is listed as not applicable. The registry enrollment is 36. The primary outcome is continuous and is summarized as a mean with standard deviation. The listed arms are salsalate, carvedilol, and placebo; the posted primary results include 11 participants for salsalate, 12 for carvedilol, and 12 for placebo.

The intervention descriptions combine an intravenous Intralipid 20% infusion with study tablets. Each description specifies a 24-hour infusion. The salsalate arm description gives a starting tablet dose of 750 mg twice daily, with escalation after two weeks if the subject has no side effects. The carvedilol description gives a starting dose of 3.125 mg twice daily, with a similar stated escalation condition. The placebo description also describes twice-daily tablets and dose escalation after two weeks. Further details of the salsalate and carvedilol descriptions are truncated in the registry record, so their complete treatment schedules are not reported in the registry record.

The primary measure is systolic blood-pressure change from pre-dose at baseline to four hours during the Intralipid infusion. The endpoint description says blood pressure was measured in triplicate with a manual cuff before dosing and every four hours during the 24-hour infusion, with subjects supine. The posted comparison estimates are unadjusted mean differences against placebo. The registry record does not report the trial’s original sample-size assumptions, a detailed statistical analysis plan, or the method used to handle all missing data. It also does not report whether any interim analyses were planned or conducted.

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: All subjects will receive IV Intralipid (20% solution at 20 ml/hour) prior to randomization.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One subject in the salsalate arm withdrew from the study was not included in the baseline analysis population.

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.

Population: All but one of the subjects that completed the study were included in the baseline analysis. No data was recorded for one subject who withdrew from the study.

6. Primary Endpoint

The registry lists the primary outcome as Change in Systolic Blood Pressure., measured over Pre-dose (Baseline), within 4 hours at Baseline visit.

The primary endpoint is change in systolic blood pressure, measured in mmHg. Systolic pressure is the pressure generated when the heart pumps blood through the arteries. The registry defines the change for this outcome as the difference between the pre-dose reading at the baseline visit and the reading four hours into the Intralipid infusion. It describes triplicate manual-cuff measurements in the supine position before dosing and at four-hour intervals during the infusion.

This endpoint gives a continuous measure of blood-pressure response at a specified point during the infusion. Reporting a mean and standard deviation describes both the average change in each arm and the variation among the measured values. Comparing each active-treatment arm with placebo provides an estimate of the difference between their average changes. That comparison is useful for quantifying the observed group contrast, but it does not by itself establish why the groups differed or whether the difference would persist at other times.

The reported endpoint is specific to systolic pressure at the stated assessment. Although the registry lists other outcomes, including diastolic pressure and measures related to vascular function, inflammation, free fatty acid levels, and oxidative stress, those outcomes are not part of the primary estimate. Results for the listed secondary outcomes are not reported in the registry record.

7. Results Posted in the Registry

• Salsalate: mean 15.37 versus 10.25 on control; difference 5.12 (95% CI -3.93 to 14.17), standardized effect d = 0.46; z-test p = 0.268.
• Carvedilol: mean 10.04 versus 10.25 on control; difference -0.21 (95% CI -8.99 to 8.57), standardized effect d = -0.02; z-test p = 0.963.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change describe?

The primary outcome is continuous, so the registry reports each group’s mean change and standard deviation. A mean is the average of the measured changes in that group. The standard deviation describes how spread out individual observations are around the group mean. It is not the uncertainty in the mean itself: uncertainty in a mean comparison also depends on the number of observations and the variability in the groups.

The reported group means are 15.37 mmHg for salsalate, 10.04 mmHg for carvedilol, and 10.25 mmHg for placebo. The associated standard deviations are 9.15, 8.72, and 12.83, respectively. These summaries describe the groups at the primary assessment. A difference between two group means is a contrast in average changes, not a comparison of every participant’s response.

How should the treatment contrasts be read?

The registry comparisons use placebo as the reference. The mean difference is the active-arm mean minus the placebo mean. For salsalate, that estimate is 5.12 mmHg; for carvedilol, it is -0.21 mmHg. A positive estimate means the reported mean change is higher in the active arm than in placebo, while a negative estimate means it is lower. The sign describes the direction of this defined contrast; it does not establish a causal mechanism or a broader clinical interpretation.

The analysis also reports pooled standard deviations and standardized effect estimates. A pooled standard deviation combines information about variability across the compared groups for the purpose of expressing a difference relative to the observed spread. A standardized effect expresses the mean difference in standard-deviation units, which can aid comparison across measures with different units. For salsalate, the posted standardized estimate is 0.456; for carvedilol, it is -0.019. These are summaries of the observed contrasts, not separate clinical outcomes.

What do confidence intervals and p-values add?

A confidence interval communicates uncertainty around an estimated difference. In general, it is constructed by a method that would capture the underlying parameter at the stated rate over repeated use of the method, if its assumptions hold. For salsalate, the reported interval is -3.932 to 14.17 mmHg; for carvedilol, it is -8.987 to 8.567 mmHg. Both intervals include zero, the value corresponding to no mean difference between the compared arms. Their widths indicate that the estimates are not precise enough to isolate a narrow range of plausible differences.

The unadjusted p-values are 0.268 for salsalate and 0.963 for carvedilol. In general, a p-value is calculated under a null hypothesis and a statistical model; it describes how unusual data at least as inconsistent with that null would be under those assumptions. It does not measure the size or importance of an effect, and it does not give the probability that the null hypothesis is true. The posted p-values are explicitly unadjusted, and the registry record does not report multiplicity correction.

What is the role of the planning calculations?

The sample-size illustrations use the observed effect as a starting point and show planning values for detecting the stated fraction of that effect. They assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. These are planning calculations based on the observed estimates, not a report of the trial’s original design process. The original sample-size justification and design assumptions are not reported in the registry record.

The calculations use the posted effect and variability summaries to illustrate how a future comparison’s required number of participants per arm changes with the effect being targeted. Because the observed carvedilol-versus-placebo mean difference is very close to zero, its planning values are extremely large. Such values are sensitive to the observed estimate and should not be treated as reliable forecasts of a future trial’s needs. The calculations do not change or strengthen the evidence in the completed study.

Why can variability matter?

In general, greater variability makes a group mean harder to estimate precisely, while a larger sample can improve precision if other conditions remain comparable. When data vary more than the chosen statistical model anticipates, standard errors and tests can be misleading unless the analysis accounts for that over-dispersion. The primary results report standard deviations, but the registry record does not identify a separate over-dispersion model or a more detailed model specification. The comparisons are therefore best interpreted as the posted unadjusted mean contrasts with their reported uncertainty.

10. Confidence Intervals and Precision

The confidence intervals communicate substantial uncertainty in both active-treatment comparisons. For salsalate versus placebo, the estimated mean difference is 5.12 mmHg, and the 95% confidence interval extends from -3.932 to 14.17 mmHg. For carvedilol versus placebo, the estimated mean difference is -0.21 mmHg, with a 95% confidence interval from -8.987 to 8.567 mmHg. Each interval includes zero, so neither estimate rules out no mean difference under the reported interval method.

The intervals also extend in both directions around zero. The salsalate interval permits a negative difference as well as a positive one, and the carvedilol interval likewise permits differences in either direction. This breadth means that the estimates do not tightly distinguish among a range of possible treatment-versus-placebo contrasts. A point estimate alone can obscure this uncertainty; the interval should be considered alongside it.

Precision depends on the amount of information in the comparison and the variability in the measured outcome. The posted arm sizes are 11 for salsalate, 12 for carvedilol, and 12 for placebo. The group standard deviations are 9.15, 8.72, and 12.83, respectively. These quantities help contextualize why the reported estimates have uncertainty, but they do not eliminate it. The registry record does not report an adjusted confidence interval or a complete analysis plan that would clarify other sources of uncertainty.

A confidence interval is not a guarantee that the true effect lies within its endpoints, nor does it assign a probability to a particular effect after observing the data. It describes uncertainty under the method and assumptions used. Here, the posted intervals are most useful as a reminder that the mean differences are not estimated precisely. They do not justify treating the point estimates as established effects or treating a value near zero as proof of no difference.

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 sample-size figures are planning illustrations expressed as participants per arm for 80% power and participants per arm for 90% power. They are not total event counts. The calculations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They consider detecting the stated fraction of the observed effect. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

For the salsalate comparison, planning for 100% of the observed effect gives 76 participants per arm for 80% power and 102 participants per arm for 90% power. Planning for 75% of the observed effect gives 135 participants per arm for 80% power and 180 participants per arm for 90% power. Planning for 50% of the observed effect gives 303 participants per arm for 80% power and 405 participants per arm for 90% power.

For the carvedilol comparison, planning for 100% of the observed effect gives 42,831 participants per arm for 80% power and 57,338 participants per arm for 90% power. Planning for 75% of the observed effect gives 76,143 participants per arm for 80% power and 101,934 participants per arm for 90% power. Planning for 50% of the observed effect gives 171,321 participants per arm for 80% power and 229,350 participants per arm for 90% power.

In general, the 80% column describes a planning target for a design intended to have an 80% chance of detecting the specified effect under the stated assumptions; the 90% column uses a higher target. Smaller effects need more participants to detect under otherwise similar assumptions, which is why the planning values increase when the targeted fraction is smaller. The very large carvedilol values reflect the small observed mean difference used in the calculation. These are planning illustrations based on observed effects, not observed power in the completed trial.

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 = 5.120; pooled standard deviation σ = 11.229.
2. n = 2 × (1.96 + 0.842)² × 11.229² / 5.120² = 75.5, rounded up to 76 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 <- 5.12                      # observed difference in means
sigma <- 11.2290501230811                     # 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(2406586)
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 = 76 (80% power), 102 (90% power)
 75% of observed effect: n per arm = 135 (80% power), 180 (90% power)
 50% of observed effect: n per arm = 303 (80% power), 405 (90% power)
power.t.test: 76.5 
Simulated power at n = 76 per arm: 0.799 (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. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary systolic blood-pressure outcome and multiple secondary outcomes, including diastolic blood pressure, oxidative stress markers, augmentation index, inflammatory biomarkers, free fatty acid levels, and pulse wave velocity. It reports 23 outcome measures, while seven secondary outcome titles are listed in the record. Results for those secondary outcomes are not reported in the registry record for this analysis.

The two posted primary comparisons have unadjusted p-values. The registry record does not report whether a multiplicity adjustment was planned or applied, whether the outcomes followed a testing hierarchy, or how the primary and secondary tests were intended to be interpreted together. When many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. In general, multiplicity procedures address that issue by controlling a chosen error criterion across a family of tests. No such procedure is reported, so the posted p-values should be understood as unadjusted.

The endpoint description states that one subject in the salsalate arm withdrew and was not included in the baseline analysis population. The posted arm result for salsalate includes 11 participants; the registry does not provide a fuller account of the relationship between that analysis population and all randomized participants. The record does not report a complete analysis-population definition, an intention-to-treat statement, or a detailed method for handling missing measurements or withdrawals. It is therefore not possible to determine from the registry record how missing post-baseline data were handled or whether other exclusions occurred.

The registry record also does not report the original statistical analysis plan, interim-analysis procedures, or a prespecified sample-size justification. These omissions limit assessment of whether the posted comparisons follow a planned analysis and how all outcomes were handled. They do not alter the reported estimates, but they constrain the degree to which the analysis process can be independently evaluated.

14. 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 5% reporting threshold.

The registry reports serious adverse events for the salsalate, carvedilol, and placebo groups. Each group lists 12 participants at risk and 0 serious adverse events. No serious adverse-event terms are listed. These entries mean that the posted serious-event counts are zero for the groups as recorded; they do not establish that no adverse events of any kind occurred.

The record also lists 12 participants at risk and 0 other, non-serious adverse events in each group. Death counts are null, rather than stated as zero. A null entry does not supply a count; deaths are not reported in the registry record. The adverse-event figures should be read as registry-reported counts, not as a complete account of tolerability or as a comparison powered to detect differences in safety.

The registry record does not provide further detail in the listed safety data about event definitions, collection procedures, exposure duration for each group, or the handling of events after withdrawal. The figures therefore describe only the posted serious and other adverse-event counts and their recorded at-risk group sizes.

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

The primary results quantify mean systolic blood-pressure change from pre-dose to four hours during Intralipid infusion and compare each active-treatment arm with placebo. The salsalate estimate is a 5.12 mmHg higher mean change than placebo, while the carvedilol estimate is a -0.21 mmHg mean difference. Both confidence intervals include zero and span values on either side of it. The posted data therefore leave considerable uncertainty about the direction and magnitude of each mean contrast.

These findings concern one defined outcome at one assessment in a study of obese, normotensive, healthy subjects. They do not establish results for the full infusion period, for later follow-up, or for the broader collection of physiological outcomes described in the study purpose. The registry lists secondary outcome titles but does not report their results in the record available for this analysis.

The estimates should not be read as a statement that a treatment works or does not work. A nonsignificant unadjusted p-value does not demonstrate equivalence, and a point estimate is not a definitive treatment effect. The confidence intervals include both no difference and potentially meaningful differences in either direction, while the registry does not supply a threshold for clinical importance. The results are descriptive estimates with uncertainty, not medical advice or a basis for treatment decisions.

The completed study’s registry record gives useful details about the endpoint, group summaries, and unadjusted comparisons. At the same time, the absence of a reported analysis plan, full missing-data methods, multiplicity approach, and original sample-size rationale limits interpretation of the analysis process. The narrow primary measure and incomplete reporting of secondary results also mean the wider biological questions remain unanswered by these posted primary estimates alone.

16. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between an estimated effect and a precise estimate. The salsalate comparison has a positive point estimate, while the carvedilol estimate is close to zero. Yet both confidence intervals are wide and cross zero. Reading only the point estimates would miss how much uncertainty remains; reading only the p-values would also obscure the range of differences compatible with the reported data.

The study also demonstrates why outcome definition matters. Its primary endpoint is not a general blood-pressure result, but a change from pre-dose to four hours during a specified infusion. The timing, measurement method, and population define what the comparison addresses. Results at this assessment cannot automatically be extended to other times, other outcomes, or populations not described in the registry record.

Finally, the sample-size illustrations show how planning values can be strongly affected by the observed effect used as their basis. The carvedilol estimate is very close to zero, producing extremely large planning values when that observed effect is used. This is a statistical illustration, not a recommendation for a future trial size. The registry’s missing original design justification and analysis details make it especially important to distinguish these retrospective planning calculations from the completed study’s actual design.

17. 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 primary outcome is narrowly defined as the systolic blood-pressure change from pre-dose to four hours during Intralipid infusion. Although measurements were described at regular intervals during the 24-hour infusion, the primary result discussed is for the four-hour assessment. It does not summarize the full time course. The listed study purpose also covers several physiological domains, but corresponding results are not reported in the registry record.

The comparisons are unadjusted and have confidence intervals that include zero. Their precision is limited, and the registry record does not state a clinical-importance threshold that would help contextualize the range of differences. The small posted arm sizes are 11 for salsalate and 12 each for carvedilol and placebo. The sample-size illustrations are based on the observed comparisons and should not be mistaken for the original design justification, which is not reported in the registry record.

The record notes a salsalate-arm withdrawal excluded from the baseline analysis population, but does not describe comprehensive missing-data methods, a full analysis-population definition, or how incomplete post-baseline measurements were handled. It also does not report a multiplicity procedure despite listing multiple outcomes. The trial’s detailed statistical analysis plan and interim-analysis procedures are not reported in the registry record.

Intervention descriptions for the active arms are truncated, so complete treatment schedules are not available in the registry record. The safety entries report zero serious and other adverse events in each listed group, but do not provide event definitions or further collection details; death counts are not reported. These reporting limits prevent broader conclusions about safety or the full conduct of the study.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Free Fatty Acids-Induced Hypertension in Obese Subjects (Aim #2) — NCT02406586.
• Registry record last updated 2019-01-08; status last verified 2018-12.
• Results first posted 2015-05-28.
• 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.

21. Record Summary

The registry record identifies NCT02406586 as a completed, randomized, double-masked, parallel-group study sponsored by Emory University. Enrollment is listed as 36, and the study phase is not applicable. The population is described as obese, normotensive, healthy subjects. The intervention arms are salsalate and carvedilol, compared with placebo, alongside an Intralipid 20% infusion.

The primary outcome is mean change in systolic blood pressure from pre-dose at baseline to four hours during infusion. The posted mean differences versus placebo are 5.12 mmHg for salsalate and -0.21 mmHg for carvedilol; both reported confidence intervals include zero. The record also lists secondary outcomes, but their results are not reported in the registry record for this analysis.

The registry reports zero serious and zero other adverse events in each listed group; death counts are not reported. The original sample-size rationale, detailed analysis plan, multiplicity approach, and comprehensive missing-data methods are not reported in the registry record.