Losartan for Improved Vascular Endothelial Function After Preeclampsia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Losartan for Improved Vascular Endothelial Function After Preeclampsia (NCT04632589), a randomized early/phase 1 study. The primary outcome is Cutaneous Conductance (%Maximum) Response to Acetylcholine.

2. Clinical Question

The study addresses a proposed mechanism of persistent vascular changes after preeclampsia. The registry describes skin blood vessels as a representative vascular bed and says that intradermal microdialysis was used to deliver agents locally while laser-Doppler flowmetry measured blood flow. Blood was also collected to examine inflammatory cell responses, but no secondary results are posted in the registry record.

This is a physiological endpoint question, not a test of later cardiovascular disease events. The registry record does not report clinical cardiovascular outcomes as trial endpoints. The posted comparison concerns the measured skin-vessel response following the two treatment periods. It can describe the observed difference in this small group, but it does not by itself establish the effect of treatment on long-term health outcomes or explain all mechanisms underlying vascular changes after preeclampsia.

3. Trial Design

This was a randomized, triple-masked, crossover study recorded as early phase 1. The registry lists an enrollment of 11 and a completed status. The study began on 2020-11-22, and the primary completion date was 2024-06-30. The record describes all participants as completing both treatments in the randomized, blinded, crossover design.

Each participant received losartan and placebo during separate treatment periods. Losartan was a daily oral 50mg/day tablet for 6 weeks; placebo was a daily oral tablet for 6 weeks. Because the same participants experienced both treatment conditions, the design differs from a parallel-group trial in which each participant receives only one assigned treatment. Randomization and masking are recorded, but details of treatment sequence, allocation procedures, and what the triple masking covered are not reported in the registry record.

The primary outcome was assessed immediately following 6 weeks of oral treatment. The registry describes measurement of cutaneous vascular response using laser-Doppler flowmetry during intradermal microdialysis. Acetylcholine was delivered alone or with L-NAME, and cutaneous conductance was calculated using laser-Doppler flux and mean arterial pressure, then normalized to site-specific maximal dilation.

The registry record does not report a washout interval, the timing between treatment periods, or any restrictions on other treatments. It also does not report the original sample-size justification or detailed statistical analysis plan. Those omissions matter when interpreting a crossover study, because treatment sequence, period effects, and analysis of within-participant measurements can affect how a treatment contrast is estimated. They cannot be reconstructed from the posted summary statistics.

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: All participants completed both treatments in randomized, blinded, cross-over design

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 Cutaneous Conductance (%Maximum) Response to Acetylcholine, measured over immediately following 6 weeks of oral treatment (losartan or placebo).

The primary endpoint is cutaneous conductance response to acetylcholine, expressed as a percentage of maximal cutaneous conductance. It assesses the vasodilator response of skin blood vessels to acetylcholine. The registry describes delivery through intradermal microdialysis and measurement with laser-Doppler flowmetry. Conductance is calculated from laser-Doppler flux and mean arterial pressure, then normalized to the maximum dilation at the measurement site.

Normalization expresses the response relative to the local maximum rather than as an unscaled flux reading. This provides a way to describe the acetylcholine response in relation to the participant's maximal cutaneous conductance at the measurement site. The endpoint is a physiological measure of vascular function in skin; it is not a direct measurement of cardiovascular events or clinical disease.

The registry lists the primary timeframe as immediately following 6 weeks of oral treatment, whether losartan or placebo. It also describes measurement after acetylcholine alone or co-infused with L-NAME. The posted primary results are a mean and standard deviation for each treatment condition, along with a mean-difference estimate and confidence interval. The record does not report separate numerical results for the acetylcholine-alone and acetylcholine-with-L-NAME conditions, so the posted summary should be interpreted as the registry's stated primary outcome rather than as a basis for reconstructing unposted component results.

7. Results Posted in the Registry

• Losartan: mean 89.40 versus 72.50 on control; difference 16.90 (95% CI 0.36 to 33.44), standardized effect d = 0.85; z-test p = 0.045.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the mean describe?

The primary outcome is a continuous measurement, and the registry identifies the summary as a mean with standard deviation. A mean is the average of the observed measurements in a treatment condition. In the posted results, the mean was 89.4% of maximal cutaneous conductance after losartan and 72.5% after placebo. These values summarize the measurements across the participants; they do not mean that every participant had that response.

The standard deviation describes the spread of individual measurements around their treatment-condition mean. The posted standard deviations were 22.6 for losartan and 16.5 for placebo. Standard deviation is not the uncertainty in the mean difference. It describes variation among measurements, whereas the confidence interval for the mean difference describes uncertainty in the estimated contrast. The registry does not provide participant-level values, so the distribution of responses and the relationship between each participant's two measurements cannot be examined from the summary alone.

How should the mean difference be read?

The posted mean difference is 16.9 percentage points, comparing losartan with placebo. It is an absolute difference on the percentage-of-maximum scale, not a relative percentage change. The point estimate gives one summary of the contrast, while the confidence interval conveys how imprecisely that contrast is estimated. For a crossover design, a mean difference might be estimated using the paired measurements from each participant. However, the registry does not state the analysis method, and the posted group means alone do not reveal whether the comparison used pairing or adjusted for other design features.

More generally, a crossover design compares treatment conditions within participants. This can reduce the influence of stable differences between participants when the analysis properly uses the repeated measurements. It also requires attention to the possibility that outcomes vary by period or that one treatment period influences another. Whether such features were assessed or modeled is not reported in the registry record. The description of randomized, blinded crossover treatment does not supply those analytical details.

What does a confidence interval communicate?

A confidence interval is a range of values compatible with the data and the statistical method used to estimate the effect. In repeated use of the same method under its assumptions, confidence intervals have a long-run coverage interpretation. It is not a range containing a known proportion of individual responses, and it is not a guarantee that the true effect lies within the particular interval. Here, the posted interval for the mean difference is 0.364 to 33.44. Its width signals that the estimate is uncertain; its lower endpoint is near zero, and the interval also includes substantially larger positive differences.

The statistical method used to construct that interval is not reported in the registry record. In particular, the record does not say whether the interval reflects a paired analysis appropriate to the crossover design. That missing detail limits independent evaluation of the interval's assumptions. The interval should therefore be read as the registry's posted uncertainty summary, not as a reconstruction of an analysis model.

What does the p-value add?

The unadjusted p-value is 0.045. In general, a p-value measures the compatibility of data with a null hypothesis under a chosen statistical model and its assumptions. A smaller p-value indicates that data such as those observed would be less compatible with that null model, if the assumptions hold. A p-value is not a measure of the clinical importance of an effect, is not the probability that the null is true, and does not show how likely the result is to replicate.

The term unadjusted means that the reported value is not identified as adjusted for multiple comparisons. The registry record does not describe an adjustment procedure or a full plan for handling multiple outcomes or analyses. The record lists 2 outcome measures, but no secondary results are posted. It is therefore not possible to establish from the record whether other analyses were planned, how many comparisons were considered, or how the primary p-value should be interpreted in the context of all analyses.

Why can over-dispersion matter?

General statistical explanation: over-dispersion occurs when observed variation is greater than a model assumes. If a model underestimates variation, standard errors may be too small and confidence intervals too narrow; tests may then appear more decisive than the data warrant. Conversely, a model that accounts for the variation can produce wider uncertainty. The posted endpoint is continuous and the registry reports standard deviations, but it does not report whether over-dispersion was assessed or whether a model requiring that assessment was used. No claim about over-dispersion in this trial can be made from the record.

The registry reports no posted analyses beyond the primary comparison, and the underlying analysis specification is not reported in the registry record. As a result, the mean, standard deviations, confidence interval, and unadjusted p-value can be explained, but the model, assumptions, handling of repeated measurements, and any diagnostic checks cannot be verified from the posted information.

10. Confidence Intervals and Precision

The estimated losartan-versus-placebo mean difference is 16.9 percentage points. The posted confidence interval extends from 0.364 to 33.44. The interval is wide relative to the point estimate, indicating that the data do not pin down a single precise value for the difference. Values near the lower endpoint and considerably larger positive differences are both compatible with the reported interval under the method used.

The lower endpoint is close to zero, so the data provide limited precision about whether the contrast is small or more substantial. The unadjusted p-value is 0.045, but that value does not remove the uncertainty conveyed by the confidence interval. Nor does it address uncertainty about the analysis method, which is not reported in the registry record. The interval should be interpreted as the registry's posted estimate of statistical uncertainty, with its underlying method not available for review in the record.

The spread of measurements also matters for precision. The standard deviation was 22.6 after losartan and 16.5 after placebo, while the sample included 11 participants who completed both conditions. Standard deviations describe variation in the measurements; they are not confidence limits for the mean or mean difference. Because the participant-level paired measurements are not posted, readers cannot evaluate how strongly each person's values under the two treatments were related or how that relation affected the precision of the contrast.

Thus, the result identifies a positive estimated difference in this small study, but the interval leaves substantial uncertainty about its magnitude. Replication and fuller reporting of the analysis would help clarify how consistently the measured contrast might be estimated.

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 based on the observed mean difference of 16.9, not a report of the trial's original design calculation. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrations consider effects equal to 100%, 75%, and 50% of the observed effect. The planning counts are participants per arm, not total events.

For an assumed effect equal to 100% of the observed effect, the illustration gives 22 participants per arm for 80% power and 29 participants per arm for 90% power. For 75% of the observed effect, it gives 39 participants per arm for 80% power and 52 participants per arm for 90% power. For 50% of the observed effect, it gives 87 participants per arm for 80% power and 116 participants per arm for 90% power.

In plain language, the 80% power column describes the planned sample size that, under the stated assumptions and effect size, would give an 80% chance of detecting that effect using the specified test. The 90% power column uses a higher target chance of detection, so it requires more participants under the same assumptions. Smaller effects are harder to distinguish from random variation and therefore require more participants in these illustrations.

These are not observed power figures. They are hypothetical planning calculations based on the effect estimated in this small trial. The registry's original sample-size assumptions and justification are not reported in the registry record, and the illustrations should not be treated as evidence about the study's original design process.

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 = 16.900; pooled standard deviation σ = 19.786.
2. n = 2 × (1.96 + 0.842)² × 19.786² / 16.900² = 21.5, rounded up to 22 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 <- 16.9                      # observed difference in means
sigma <- 19.7864852866799                     # 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(4632589)
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 = 22 (80% power), 29 (90% power)
 75% of observed effect: n per arm = 39 (80% power), 52 (90% power)
 50% of observed effect: n per arm = 87 (80% power), 116 (90% power)
power.t.test: 22.5 
Simulated power at n = 22 per arm: 0.787 (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 2 outcome measures and posts a primary outcome comparison, but no secondary results are posted. The record identifies the primary p-value as unadjusted. It does not report a multiplicity plan, any correction for multiple comparisons, or how different outcomes or analyses were prioritized. Without that information, the effect of considering multiple possible comparisons on the interpretation of the p-value cannot be assessed.

The registry describes all participants as completing both treatment periods in the randomized, blinded, crossover design. This indicates completion of both treatments for the stated primary population. It does not provide a participant flow account, a separate analysis population definition, or information about exclusions from particular analyses. The record does not report imputation, missing-data methods, or whether any outcome measurements were unavailable despite treatment completion.

The statistical model and analysis details are also not reported in the registry record. In particular, the record does not describe the handling of the paired measurements, treatment sequence, period effects, or possible carryover. It does not say whether the analysis followed an intention-to-treat, per-protocol, or other named approach. These are distinct considerations: completion of both treatment periods is reported, but the precise analysis population and model cannot be inferred from that statement.

Consequently, the posted mean difference, confidence interval, and unadjusted p-value can be read as the registry's primary comparison, while the multiplicity strategy, missing-data handling, and full analysis population remain unclear. No further analysis decisions should be presumed.

14. 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.

For losartan, 11 participants were listed as at risk for serious adverse events and 0 were affected; 11 were listed as at risk for other adverse events and 0 were affected. The registry reports 0 deaths in this group. For placebo, 11 participants were listed as at risk for serious adverse events and 0 were affected; 11 were listed as at risk for other adverse events and 0 were affected. The registry reports 0 deaths in this group.

These are event counts recorded during the trial, not estimates of the probability of an adverse event in a broader population. A count of zero means no events were recorded among the listed participants at risk; it does not establish that an event is impossible or rule out uncommon events. The relatively small number of participants also limits how much the trial can say about safety. The registry does not list any top serious adverse event terms.

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

The posted results show that the mean cutaneous conductance response to acetylcholine was higher after the losartan treatment period than after the placebo period in the 11 participants who completed both treatments. The estimated mean difference was 16.9 percentage points, with a confidence interval from 0.364 to 33.44 and an unadjusted p-value of 0.045. These figures describe the measured physiological endpoint in this study.

They do not establish that losartan changes long-term cardiovascular outcomes after preeclampsia. The primary endpoint is a skin-vessel response measured immediately following treatment, not a clinical cardiovascular event. The registry's rationale discusses persistent vascular damage and inflammation as possible mechanisms, but the posted primary comparison alone cannot establish a mechanism or show that any measured change translates into a later health benefit.

The result also does not establish a precise or universally applicable effect. The study enrolled 11 participants, the confidence interval allows a range of possible effect sizes, and the record does not report the full statistical analysis method. The crossover design can make within-participant comparisons informative, but the record does not say how pairing, treatment order, or period effects were handled.

The safety counts report no serious adverse events, other adverse events, or deaths in either treatment condition among the listed participants at risk. Those observations are limited to this trial and do not determine the frequency of events beyond it. Taken together, the record supports a cautious description of the posted measurement contrast, not a treatment recommendation or a conclusion about clinical effectiveness.

16. Why This Trial Matters Statistically

This trial is statistically interesting because its randomized crossover design exposes each participant to both treatment conditions. In general, comparing a participant with themselves can reduce the influence of stable between-person differences. That advantage depends on appropriate analysis and on design features such as treatment sequence and period effects; how those issues were handled is not reported in the registry record.

The result also illustrates the distinction between an estimated effect and its precision. The mean difference is positive, and the unadjusted p-value is 0.045, yet the confidence interval extends from near zero to a substantially larger positive value. The point estimate alone would not communicate that uncertainty. Reading the estimate together with its interval and the small participant count gives a more complete account of what the data can support.

Another important statistical lesson is that a mechanistic physiological endpoint is not interchangeable with a clinical outcome. The measured skin-vessel response is relevant to the study's stated question about vascular function, but the registry does not report cardiovascular event results. Statistical evidence about a measured intermediate response should therefore not be translated into claims about clinical outcomes that were not reported.

Finally, the planning illustrations show how sample-size requirements depend on the assumed effect size and desired power. They use the observed effect as a starting point and are not the trial's original design justification. Clearer reporting of the crossover analysis, missing-data handling, and multiplicity approach would make the statistical evidence easier to evaluate and reproduce.

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 participant count was 11, and the confidence interval for the mean difference is wide. This limits precision and makes the estimate sensitive to the observed responses in a small group. The posted summary does not include participant-level paired measurements, so readers cannot assess the distribution of individual changes or how closely each person's responses under the two conditions were related.

Several design details relevant to crossover interpretation are not reported in the registry record. These include the treatment sequence, any washout interval, the timing between periods, and whether period or carryover effects were assessed. The record also does not report the statistical model or explain whether the mean difference and confidence interval account for the paired structure.

The original sample-size justification and the trial's full analysis plan are not reported in the registry record. Multiplicity handling, missing-data methods, and detailed analysis population definitions are also not reported. While the registry says all participants completed both treatments, this does not supply a full participant flow or explain whether every planned measurement was available.

The posted results concern a physiological skin-vessel endpoint immediately following treatment, and no secondary outcome results are posted. The registry record therefore does not provide a basis for assessing effects on clinical cardiovascular outcomes or for evaluating the described inflammatory measurements. These limitations do not negate the posted contrast, but they constrain how confidently it can be interpreted or generalized.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Losartan for Improved Vascular Endothelial Function After Preeclampsia — NCT04632589.
• Registry record last updated 2025-07-10; status last verified 2025-06.
• Results first posted 2025-07-10.
• 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

NCT04632589 is a completed randomized, triple-masked, early phase 1 crossover study of losartan and placebo in women who had experienced preeclampsia. The registry lists an enrollment of 11, with all participants completing both treatment periods. Losartan was taken as a daily 50mg/day oral tablet for 6 weeks; placebo was taken as a daily oral tablet for 6 weeks.

The primary endpoint was cutaneous conductance response to acetylcholine, expressed as a percentage of maximal cutaneous conductance immediately following each treatment period. The posted means were 89.4 after losartan and 72.5 after placebo, with a mean difference of 16.9, a confidence interval from 0.364 to 33.44, and an unadjusted p-value of 0.045. The registry reports no adverse events or deaths in either treatment condition among the listed participants at risk. The detailed statistical plan, original sample-size justification, and secondary results are not reported in the registry record.