The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin (NCT03869268), a randomized phase 4 study. The primary outcome is Assess Inflammatory Response to Intravenous Endotoxin.

2. Clinical Question

3. Trial Design

The registry describes a completed, randomized, unmasked, parallel-design Phase 4 study sponsored by Sheffield Teaching Hospitals NHS Foundation Trust. Enrollment was 72. The listed start date is 2019-04-24, and primary completion was 2021-12-10. The registry identifies Acute Coronary Syndrome as a condition, while the study summary describes healthy volunteers receiving medication before an experimental immune challenge.

The study summary describes two medication periods. In each period, volunteers took a medication combination for 10-14 days and then attended a hospital challenge day, when endotoxin was injected into the bloodstream and blood and urine tests followed. A second medication period and challenge took place after a minimum of five weeks. The arm descriptions outline regimens involving no drug, aspirin at different doses, ticagrelor, or combinations. They are not complete for every regimen, so details beyond the text in the registry record are not reported in the registry record.

The registry classifies the overall model as parallel, although the summary also describes participants repeating the process with a different medication combination. That description alone is not enough to reconstruct the sequence, assignment structure, or analysis of repeated observations. Those procedural details are not reported in the registry record. Masking is listed as none. The primary analysis population is described as all participants who completed one or both endotoxin challenge days; the handling of participants with only one completed day is not reported in the registry record.

The primary outcome is a continuous measure: plasma TNF-α at two hours after endotoxin. The registry posts a mean and standard deviation for each listed treatment group. The posted comparisons use No Drug as the reference. The registry record does not report the trial's original sample-size justification or a detailed 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.

Only the first 6 of 8 groups are shown.

Intervention + Endotoxin

Intervention + Endotoxin (Post Washout)

Analysis population for the primary outcome, as defined in the registry: all participants that completed one or both endotoxin challenge days

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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Assess Inflammatory Response to Intravenous Endotoxin, measured over 2 hours post endotoxin injection.

The primary endpoint is plasma TNF-α, measured two hours after an intravenous injection of endotoxin at 2 ng/kg. TNF-α is a circulating inflammatory signal, so its concentration provides one measurable indicator of the response to the challenge. As a continuous laboratory measure, it is summarized by a mean and standard deviation for each treatment group. The reported unit is pg/ml.

General statistical context: A laboratory marker can help quantify a specific biological response, but one marker is not a complete description of immune function. A measurement at a single time point captures the response at that point; it does not establish the full time course or all biological effects. The study also posted secondary measures, including CRP, leukocyte count, and TXB2, but the primary question is specifically about TNF-α at two hours.

The endpoint is useful for asking whether the medication regimens are associated with differences in the measured response under a controlled endotoxin challenge. It is not a clinical endpoint such as heart attack, bleeding, or survival. The registry record does not report a clinically meaningful threshold for TNF-α or a target difference that would define an important effect. Interpretation therefore centers on the observed group means and their uncertainty, rather than a threshold for clinical benefit.

7. Results Posted in the Registry

• No Drug Plus Loading Dose Ticagrelor 180mg: mean 111.05 versus 167.53 on control; difference -56.48 (95% CI -172.93 to 59.97), standardized effect d = -0.33; z-test p = 0.342.
• Aspirin 20mg BD: mean 254.92 versus 167.53 on control; difference 87.39 (95% CI -55.79 to 230.57), standardized effect d = 0.41; z-test p = 0.232.
• Aspirin 20mg BD & Loading Dose Ticagrelor 180mg: mean 128.73 versus 167.53 on control; difference -38.80 (95% CI -156.18 to 78.58), standardized effect d = -0.22; z-test p = 0.517.
• Aspirin 75mg OD no Loading Dose of Ticagrelor: mean 103.72 versus 167.53 on control; difference -63.81 (95% CI -176.19 to 48.57), standardized effect d = -0.38; z-test p = 0.266.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Serum CRP Changes

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • No Drug Plus Loading Dose Ticagrelor 180mg: mean 3.00 versus 2.84 on control; difference 0.16 (95% CI -1.16 to 1.48), standardized effect d = 0.08; z-test p = 0.812.
  • Aspirin 20mg BD: mean 3.61 versus 2.84 on control; difference 0.77 (95% CI -0.59 to 2.13), standardized effect d = 0.37; z-test p = 0.267.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between No Drug Plus Loading Dose Ticagrelor 180mg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aspirin 20mg BD and the control. The interval gives the range of effects that remain compatible with the data.

Leukocyte Count

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • No Drug Plus Loading Dose Ticagrelor 180mg: mean 9.32 versus 9.28 on control; difference 0.04 (95% CI -1.97 to 2.05), standardized effect d = 0.01; z-test p = 0.969.
  • Aspirin 20mg BD: mean 10.77 versus 9.28 on control; difference 1.49 (95% CI -0.58 to 3.56), standardized effect d = 0.48; z-test p = 0.157.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between No Drug Plus Loading Dose Ticagrelor 180mg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aspirin 20mg BD and the control. The interval gives the range of effects that remain compatible with the data.

Serum TXB2

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • No Drug Plus Loading Dose Ticagrelor 180mg: mean 274,473 versus 389,904 on control; difference -115,431 (95% CI -320,357 to 89,495), standardized effect d = -0.39; z-test p = 0.270.
  • Aspirin 20mg BD: mean 19,334 versus 389,904 on control; difference -370,570 (95% CI -546,315 to -194,825), standardized effect d = -1.48; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between No Drug Plus Loading Dose Ticagrelor 180mg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Aspirin 20mg BD than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary endpoints broaden the biological picture beyond the primary TNF-α measurement. They include CRP, leukocyte count, and TXB2, each summarized as a continuous outcome over the stated post-endotoxin timeframe. The overall pattern is not uniform: posted group means vary across regimens, and the degree and direction of variation differ by marker. This makes the secondary measures useful as complementary descriptions, but they do not form a single consistent confirmatory signal in the registry record.

These outcomes relate to the primary result by measuring other aspects of the response or medication-associated biology. They cannot replace the primary endpoint or make an imprecise primary comparison precise. The secondary record posts recalculated comparisons for only a subset of the listed treatment groups for each endpoint, rather than a reported analysis across every regimen. Formal sponsor analyses are not reported in the registry record.

Unadjusted secondary results carry less inferential weight because several endpoints and comparisons create multiple opportunities for apparently notable findings. Without a reported multiplicity plan, a low unadjusted p-value should be treated as exploratory rather than as standalone confirmation. The registry record does not report that multiplicity was controlled. In addition, the group sizes are small and some endpoint denominators differ from those for the primary outcome, which makes direct cross-endpoint pattern matching less secure.

General statistical context: Multiple biomarkers can help characterize a biological response, but each tests a distinct question and may have different variability and measurement properties. Consistency across outcomes can be informative when prespecified and analyzed with an appropriate plan; selecting a favorable result after examining many outcomes can exaggerate apparent evidence. The posted secondary summaries are best read as descriptive context that may motivate further study, not as definitive evidence that the same effect is present across biological measures.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Serum CRP Changes
• Leukocyte Count
• Serum TXB2

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the posted group summaries are means with standard deviations. A mean describes the center of the observed measurements in a group; a standard deviation describes how dispersed the individual measurements are around that group mean. These answer different questions. The standard deviation is not the uncertainty in the mean, and it should not be read as a confidence interval for the group average.

What does a mean difference represent?

The posted comparisons express each treatment-group mean relative to the No Drug mean. The mean difference is the treatment-group mean minus the reference-group mean. A negative estimate means the treatment group had a lower observed mean; a positive estimate means it had a higher observed mean. For example, the estimate for aspirin 75 mg once daily with a ticagrelor loading dose is -94.58 pg/ml. This is a difference between observed group averages, not a percentage change or an adjusted treatment effect.

The registry record also gives pooled standard deviations and standardized effect sizes for these comparisons. General statistical context: A pooled standard deviation combines information about within-group spread for a two-group comparison; a standardized effect expresses the mean difference relative to that spread. Standardization can help describe magnitude on a common scale, but it does not resolve uncertainty, confounding, or multiplicity. The effect sizes posted for this study are based on small groups and should be read as descriptive estimates rather than stable inputs for future planning.

How should the confidence intervals be understood?

A confidence interval describes uncertainty around an estimated quantity under the statistical procedure used. A wide interval means the data are compatible with a broad range of values. For the primary comparisons, the posted intervals span both negative and positive values, and each includes zero. Thus, the observations do not precisely distinguish a lower mean from no difference or, for some intervals, a higher mean. A confidence interval is not a guarantee that the true value lies within its endpoints, and it does not express the probability that a particular treatment effect is true.

The intervals and p-values are unadjusted recalculations based on posted summary statistics. The registry record does not report sponsor analyses for the primary outcome. It also does not report the test specification, any covariate adjustment, or how repeated measurements across challenge days were incorporated. Those details matter: a simple comparison of group summaries may not reflect a model that accounts for within-participant correlation or the trial's assignment structure.

Why does variation matter?

General statistical context: When observations vary considerably within groups, the group means are less precisely estimated for a given group size. This study's primary standard deviations are substantial relative to the means, while the group sizes are modest. That combination helps explain why the confidence intervals are broad. A small p-value is not a measure of effect size, and a larger p-value does not show that there is no effect; both should be interpreted alongside the estimated difference and interval.

Another general issue is over-dispersion: it occurs when observed variability is greater than a model expects. In continuous outcomes, unusually high variability can make simple model-based standard errors and intervals unreliable if the model does not account for it. The posted summaries show wide spread, but the registry record does not report a formal assessment of over-dispersion or a model designed to address it. It is therefore appropriate to treat the recalculated comparisons as basic, unadjusted descriptions.

What is and is not specified?

The registry identifies randomization, no masking, a parallel model, and the analysis population as participants completing one or both challenge days. However, the detailed randomization procedure, allocation concealment, analysis model, missing-data method, and treatment of repeated challenge observations are not reported in the registry record. The record also does not report a prespecified multiplicity strategy or a primary sample-size justification. The absence of those details limits reconstruction of the intended inferential analysis. It does not invalidate the group summaries, but it means they should not be mistaken for a fully documented confirmatory analysis.

The registry classifies the outcome parameter as a mean and its dispersion as a standard deviation. The recalculated pairwise results are simple unadjusted comparisons, rather than an asserted reconstruction of an unavailable sponsor model. Since there is no discrepancy flagged in the registry record, these calculations can be read as summaries of the posted data; no claim is made that they reproduce an unpublished analysis. The distinction matters because a protocol-based analysis may use design features not recoverable from the group-level summaries alone.

11. Confidence Intervals and Precision

The primary estimates are not precise. For the seven posted comparisons, confidence intervals are broad and include zero. Their endpoints span both lower and higher values relative to the No Drug mean in most cases; the interval for aspirin 75 mg once daily with a ticagrelor loading dose reaches 2.846 pg/ml at its upper end. The point estimate for that comparison is -94.58 pg/ml, but the interval ranges from -192.0 to 2.846 pg/ml. The data therefore do not tightly locate the difference for that regimen.

The number of participants in each primary comparison is modest: the No Drug group has 17.0 participants, and treatment-group counts range from 14.0 to 17.0. The standard deviations also indicate broad participant-to-participant variation. Both features contribute to uncertainty around the estimated means and differences. The interval, not the point estimate alone, conveys how much the data leave unresolved.

General statistical context: An interval that includes zero is compatible with no mean difference under the calculation used, but it can also include nonzero differences. It is not evidence that the groups are identical. A narrow interval would support a more precise estimate; these intervals do not provide that degree of precision. Conversely, the observed estimates should not be treated as exact values for the underlying effects.

The confidence intervals are unadjusted recalculations from summary statistics. They do not reflect a reported sponsor model, multiplicity correction, or a documented method for accounting for repeated challenge days. The registry record does not report those analysis details. Consequently, the intervals describe the simple pairwise comparisons as calculated, rather than all sources of uncertainty that might be addressed by a prespecified trial analysis.

12. 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 planning figures are participants per arm, not total participants or total events. The outcomes in this study are continuous; the event-count convention for time-to-event outcomes does not apply. The calculations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario targets a stated fraction of the observed effect: 100%, 75%, or 50% of that effect. The trial's original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the estimated participants per arm for a future two-arm comparison to have an 80% chance of detecting the specified effect, under the stated planning assumptions. The 90% power column gives the corresponding per-arm estimate for a 90% chance. Power is a property of a planned study under assumptions; it is not a measure of whether the observed result is true or important.

Smaller target effects require more participants because a smaller difference is harder to distinguish from the variability in the outcome. The rows for 75% and 50% of the observed effect therefore generally require larger per-arm samples than the row using the full observed effect. The estimates depend on the observed effect and variability in these small groups, so they should be treated as planning illustrations rather than definitive design recommendations. They are not observed power.

The curve should be read as a visual rendering of how the planning estimate changes as the assumed effect changes. It does not add new trial observations or replace the confidence intervals for the posted results. Because the calculations are based on observed effects, a small or unstable observed difference can produce a large planning estimate; the original protocol rationale is not reported in the registry record.

13. 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 = -56.480; pooled standard deviation σ = 171.569.
2. n = 2 × (1.96 + 0.842)² × 171.569² / -56.480² = 144.9, rounded up to 145 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 <- -56.48                      # observed difference in means
sigma <- 171.56860363959                     # 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(3869268)
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 = 145 (80% power), 194 (90% power)
 75% of observed effect: n per arm = 258 (80% power), 345 (90% power)
 50% of observed effect: n per arm = 580 (80% power), 776 (90% power)
power.t.test: 145.8 
Simulated power at n = 145 per arm: 0.798 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry posts multiple primary comparisons against the No Drug group, as well as secondary outcomes and additional treatment groups. The reported p-values for the recalculated comparisons are unadjusted. A multiplicity adjustment, prespecified testing hierarchy, or other strategy for controlling the chance of false-positive findings across these comparisons is not reported in the registry record. Thus, each p-value should be understood as a result for its individual comparison, not as an error-controlled conclusion across the full family of questions.

The registry record lists four outcome measures, with three secondary outcomes posted. It reports no sponsor analyses for the primary outcome and no reported analyses for the secondary outcomes. The reported mean differences, confidence intervals, and p-values are unadjusted recalculations from summary data. A detailed analysis plan, including whether the primary contrasts were prespecified and how secondary testing was intended to be interpreted, is not reported in the registry record.

The primary population is described as all participants who completed one or both endotoxin challenge days. That definition means the posted outcome population is not explicitly described as requiring completion of both days. The registry record does not explain how participants who completed only one challenge contributed to a treatment comparison, how incomplete outcome measurements were handled, or whether any missing-data method was used. Missing-data patterns and reasons for missingness are not reported in the registry record.

Group denominators vary across the posted outcomes. Such variation can reflect differences in which measurements are available, but the cause is not reported in the registry record. The record also does not report whether the repeated challenge observations were analyzed as independent measurements, paired observations, or with a model accounting for participant-level correlation. These omissions matter because they affect standard errors and the interpretation of treatment contrasts. The posted group summaries remain informative descriptions, but they cannot answer questions about the intended missing-data and repeated-measures strategy.

15. 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.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events in each listed group, and zero deaths in each group. The denominators at risk for serious adverse events range from 14 to 17 participants across the groups. These are counts recorded in the registry, not proof that serious harms are impossible or that treatment groups have equal safety profiles.

The registry also lists other adverse-event counts: 3 in No Drug, 3 in No Drug Plus Ticagrelor 180mg, 5 with Aspirin 20mg BD, 4 with Aspirin 20mg BD and Ticagrelor 180mg, 4 with Aspirin 75mg OD, 5 with Aspirin 75mg OD and Ticagrelor 180mg, 5 with Aspirin 300mg OD, and 2 with Aspirin 300mg OD and Ticagrelor 180mg. The record does not provide serious adverse-event terms, and the serious-event terms list is empty. It does not give details about the nature, timing, or relatedness of the other adverse events.

General statistical context: Small group sizes and low event counts provide limited ability to compare uncommon safety outcomes. These registry counts are descriptive and should not be interpreted as a reliable comparative estimate of risk. They also do not establish that an event was caused by a study regimen.

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

The posted data describe short-term inflammatory-marker responses to an endotoxin challenge after medication regimens involving aspirin and, in some groups, ticagrelor. For the primary endpoint, group means differ numerically, but the unadjusted confidence intervals are broad and include zero. The study record therefore does not provide a precise estimate of the differences between the listed regimens and No Drug.

The results do not establish that the regimens have identical effects. A non-significant unadjusted comparison can occur when an estimate is uncertain, including when the true difference is not zero. At the same time, the point estimates alone should not be treated as proof of an effect. The small group sizes, substantial variation, multiple comparisons, and absence of a reported sponsor analysis all limit the strength of conclusions that can be drawn from these summaries.

The experiment addresses a laboratory response after an induced endotoxin challenge in healthy volunteers. It is not a direct test of clinical outcomes in people with acute coronary syndrome, despite that condition being listed in the registry. TNF-α at two hours is one measure at one time point, and it does not by itself establish how the full immune response changes or what that would mean for clinical outcomes.

The registry's safety data record no serious adverse events and no deaths in the listed groups, but the numbers of participants are small and the record gives limited detail about other events. Those counts are not sufficient to establish comparative safety. The appropriate interpretation is therefore descriptive: the posted summaries show variability across regimens and substantial uncertainty, while leaving important questions about analysis, repeated measurements, missing data, and clinical relevance unresolved.

General statistical context: A controlled experimental challenge can isolate a biological response under study conditions, but transportability to different populations, settings, or outcomes must be evaluated separately. These results alone do not support a treatment recommendation or a conclusion about clinical effectiveness.

17. Why This Trial Matters Statistically

This trial raises a useful statistical question about how a biological response is measured and compared across several medication regimens. The primary endpoint is quantitative, but its high variability and the small numbers in each group make precision a central part of interpretation. Looking only at the estimated mean differences would miss how widely plausible values extend around those estimates.

The study also illustrates why the trial design and analysis details matter. The registry classifies the study as parallel, while the summary describes participants completing two medication periods separated by a minimum of five weeks and undergoing repeated challenges. Without a reported account of how assignment, sequence, and within-participant correlation were handled, simple comparisons of group summaries cannot fully reconstruct the intended analysis. The displayed results answer a limited, unadjusted question.

Multiplicity is another important feature. Several regimens are compared with a reference group, and multiple biomarkers are posted. Unadjusted p-values can be useful for exploratory description, but they do not account for the number of questions examined. A prespecified analysis plan would clarify which contrasts were primary and how secondary findings should be weighed; those details are not reported in the registry record.

The planning illustrations also show how strongly future sample requirements depend on the target effect and observed variability. They are based on observed results, not on a documented original design rationale, and should not be confused with evidence that the trial was adequately or inadequately powered. Statistically, the central lesson is that a small study can yield informative estimates while still leaving substantial uncertainty about the size and consistency of effects.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record leaves several trial-specific uncertainties. Although it identifies the study as randomized and parallel, the summary describes two medication periods and repeated endotoxin challenges. The exact assignment sequence and how the repeated observations relate to the parallel classification are not reported in the registry record. Without that information, it is not possible to determine from the posted summaries how participant-level correlation or period effects were addressed.

The group sizes for the primary endpoint are small, and the standard deviations are large relative to the means. Confidence intervals are consequently broad. The record does not report the original sample-size justification, so it is not possible to assess the planned precision or target effect from the registry description. The sample-size illustrations derived from observed results do not fill that gap.

The primary and secondary results are posted as group summaries, with unadjusted recalculated comparisons rather than sponsor-reported analyses. A detailed statistical analysis plan, multiplicity strategy, covariate adjustment, and model for repeated observations are not reported in the registry record. This limits interpretation of the p-values and intervals as a complete trial analysis.

The primary population includes participants completing one or both challenge days, but the handling of incomplete periods and missing outcome measurements is not reported. Denominators differ across outcomes, and the reasons are not described. The registry also does not report a clinically meaningful difference for TNF-α or establish how the challenge marker relates to clinical outcomes. Finally, although Acute Coronary Syndrome is listed as a condition, the study summary describes healthy volunteers. The results should therefore be understood in the context of the described experimental challenge, rather than assumed to represent clinical treatment outcomes in people with acute coronary syndrome.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin — NCT03869268.
• Registry record last updated 2025-09-11; status last verified 2025-07.
• Results first posted 2025-09-11.
• 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.

22. Record Summary

NCT03869268 is a completed, randomized, unmasked Phase 4 study sponsored by Sheffield Teaching Hospitals NHS Foundation Trust, with enrollment of 72. The registry classifies it as a parallel study and lists Acute Coronary Syndrome as a condition; the study summary describes healthy volunteers receiving medication before endotoxin challenge.

The primary endpoint is mean plasma TNF-α two hours after endotoxin injection at 2 ng/kg. The registry posts group means and standard deviations and comparisons against No Drug. All posted primary confidence intervals include zero, and the comparisons are unadjusted recalculations with no sponsor analyses reported in the registry record. Secondary endpoints include serum CRP, leukocyte count, and serum TXB2.

The posted results are descriptive and imprecise, with small groups and substantial variation. The record reports zero serious adverse events and zero deaths in each group. Details of the original sample-size justification, multiplicity approach, missing-data handling, and analysis of repeated challenge observations are not reported in the registry record.