Efficacy and Safety of Acetylcysteine for the Treatment of Acute Uncomplicated Rhinosinusitis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Acetylcysteine for the Treatment of Acute Uncomplicated Rhinosinusitis (NCT04123405), a randomized phase 3 study. The primary outcome is Mean Change From Baseline in the Daily Major Symptom Score (MSS) Over the Entire Treatment Period, Full Analysis Set.

2. Clinical Question

3. Trial Design

This was a phase 3, prospective, randomized, double-blind, placebo-controlled trial with a parallel-group design. The registry describes the study as multinational and multicenter, with four parallel groups: acetylcysteine 600 mg, acetylcysteine 1200 mg, acetylcysteine 2400 mg, and placebo. The listed enrollment was 944, and the trial status is completed. The recorded start date is 2020-10-22 and the primary completion date is 2021-04-20.

The dosing descriptions distinguish the three active-dose groups while keeping the daily tablet schedule similar. The 600 mg group took one test-product tablet and three placebo tablets per day; the 1200 mg group took two test-product tablets and two placebo tablets per day; and the 2400 mg group took four test-product tablets per day. The placebo group took four placebo tablets per day. In all groups, the tablets were taken as two tablets dissolved in a glass of water twice daily.

The registry identifies Sandoz as sponsor. It does not report country-level recruitment details, the method used to generate or conceal the random allocation, the operational details of masking, or the original sample-size justification. The fact that the trial was randomized and double-blind describes its recorded design, but does not establish those unreported implementation details. The primary endpoint was assessed in the Full Analysis Set rather than being described as an analysis of every enrolled participant. The registry definition of that set requires randomization, at least one dose, and at least one post-baseline MSS assessment.

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 were randomized in 1:1:1:1 ratio

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full-Analysis Set (FAS) included all randomized patients who received at least one dose of the trial medication and who had at least one post-baseline assessment of MSS during the double-blind treatment period.

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 Mean Change From Baseline in the Daily Major Symptom Score (MSS) Over the Entire Treatment Period, Full Analysis Set, measured over Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.

The primary endpoint is mean change from baseline in the daily Major Symptom Score (MSS), averaged over the treatment period. Baseline is Day 1, and the posted timeframe runs from Day 2 through Day 15. The MSS combines five symptoms: rhinorrhea or anterior discharge, postnasal drip, nasal congestion, headache, and facial pain or pressure. Patients rated each symptom on a four-point scale, from 0 for none or not present to 3 for severe. The five ratings are summed, giving a possible total score from 0 to 15.

The endpoint first summarizes the daily total score and then compares the average from Day 2 to Day 15 with the baseline score. A negative mean change means that the score was lower during the treatment period than at baseline. This makes the endpoint a measure of change in reported symptom severity rather than a count of symptom-free days or a time-to-event measure.

In general, a combined score can represent several related symptoms in a single continuous outcome, while retaining more gradation than a simple yes-or-no measure. Interpretation depends on how the scale is defined and on the size and precision of the observed change. The registry record does not report a threshold for a clinically important MSS change, so the posted mean differences cannot be classified against such a threshold from this record alone.

7. Results Posted in the Registry

• Group A: 600 mg Acetylcysteine: mean -4.82 versus -5.02 on control; difference 0.20 (95% CI -0.16 to 0.56), standardized effect d = 0.10; z-test p = 0.285.
• Group B: 1200 mg Acetylcysteine: mean -4.74 versus -5.02 on control; difference 0.28 (95% CI -0.08 to 0.64), standardized effect d = 0.14; z-test p = 0.130.
• Group C: 2400 mg Acetylcysteine: mean -4.78 versus -5.02 on control; difference 0.24 (95% CI -0.12 to 0.60), standardized effect d = 0.12; z-test p = 0.185.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a mean change in an MSS score. A mean describes the average value across participants, while the standard deviation describes how much individual scores vary around that average. The posted standard deviations were 1.982 for 600 mg, 1.991 for 1200 mg, 1.969 for 2400 mg, and 1.983 for placebo. In general, the standard deviation is not the same as the uncertainty of the group mean or of a between-group contrast; that uncertainty also depends on the number of participants contributing data.

What does the mean difference compare?

Each contrast compares an acetylcysteine group’s mean change with the placebo group’s mean change. The difference is oriented as acetylcysteine minus placebo. Because the outcome is a change score and negative change denotes improvement, the sign should be read in that context: a positive contrast corresponds to a less negative mean change in the acetylcysteine group than in placebo. This sign convention does not make the contrast a direct measure of clinical importance.

The contrasts and associated confidence intervals are unadjusted recalculations from the posted arm summaries. They are not identified as adjusted estimates from a registry-reported regression model or repeated-measures analysis. The record does not report a specific model for the primary endpoint, any covariates in an adjusted model, or whether the original sponsor analysis used another approach. The recalculated values should therefore be interpreted as simple comparisons of the posted group summaries.

What do the confidence intervals and p-values add?

A confidence interval expresses uncertainty around an estimated difference. In general, it shows a range of values compatible with the data under the calculation’s assumptions; it does not assign a probability that a particular fixed treatment effect lies inside the interval. Here, each interval includes zero, so the summaries do not rule out no mean difference. The intervals also include positive values and some negative values, leaving uncertainty about the direction and size of the contrast.

A p-value measures how unusual the observed data, or data more extreme, would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The p-values reported for these comparisons are unadjusted. The registry record does not report a multiplicity procedure or identify a confirmatory testing hierarchy, so these p-values should not be read as adjusted for the three dose comparisons or for the broader set of outcomes.

How should the MSS scale be understood?

The MSS adds ratings for five symptoms, each rated from 0 to 3, for a possible score from 0 to 15. The primary outcome averages daily score changes from Day 2 to Day 15 relative to Day 1. In general, summarizing repeated daily scores as an average can convey the overall course during a period, but it can obscure whether scores changed early or late, or whether participants followed different trajectories. The registry lists development of MSS over the course of the study as a secondary outcome, but numerical results for those secondary outcomes are not reported in the posted results contained in the registry record.

What assumptions are relevant?

In general, mean-based comparisons summarize the outcome as a continuous quantity and are most directly informative when the mean is meaningful for the scale and the uncertainty calculation is appropriate for the data. The registry describes the MSS as a summed score, but does not report diagnostics for its distribution, handling of repeated observations in the original analysis, or sensitivity analyses. The posted standard deviations indicate the observed spread within each group; they do not establish that all modeling assumptions were met.

The primary endpoint population is the Full Analysis Set. The record defines it as all randomized patients who received at least one dose and had at least one post-baseline MSS assessment during double-blind treatment. This is a specific analysis population, not simply everyone enrolled. The registry also lists per-protocol secondary outcomes, but it does not report per-protocol primary results in the information available for this endpoint. Missing-data methods and the number of participants excluded from each analysis population are not reported in the registry record.

10. Confidence Intervals and Precision

The mean-difference estimates are close to zero relative to their uncertainty. For 600 mg versus placebo, the estimate is 0.197 and the 95% confidence interval is -0.164 to 0.557. For 1200 mg versus placebo, the estimate is 0.279 and the interval is -0.082 to 0.639. For 2400 mg versus placebo, the estimate is 0.242 and the interval is -0.116 to 0.600. Every interval crosses zero, so the posted summaries leave uncertainty about whether the underlying mean difference is slightly negative, zero, or positive.

In general, a narrower confidence interval indicates greater precision, while a wider interval leaves a broader range of plausible values. These intervals have similar widths across the three comparisons, and none isolates a single direction of effect. Their limits should be interpreted on the MSS change scale, not as a percentage or as a probability of benefit. The registry record does not report a minimum clinically important difference, so the intervals cannot be divided into clinically meaningful and unimportant regions using a threshold from the record.

The arm-level standard deviations are near 2 score points, and the reported analysis group sizes range from 230.0 to 238.0 participants. The record does not explain every difference between the listed enrollment and analysis group counts, nor does it report confidence intervals for within-group means. Precision for the comparisons can also depend on the analysis method and missing-data handling, details not reported in the registry record. The displayed intervals are unadjusted recalculations from summary statistics and should be read as such rather than as a complete account of uncertainty under a full trial analysis plan.

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 planning figures are participants per arm, not total participants or total events. They are planning illustrations based on the observed mean difference, with separate rows planning for 100%, 75%, or 50% of that observed effect. For example, the 80% and 90% power columns give the estimated participants per arm for those respective power targets under the stated assumptions. The values are not counts of participants enrolled or analyzed in this trial.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record. These planning figures are not observed power.

In general, power is the chance that a planned analysis will detect an effect of a specified size under its assumptions if that effect is present. The 80% column represents planning for an 80% chance of detection, and the 90% column represents planning for a 90% chance, for the selected effect size and assumptions. The calculation is made separately for each dose-versus-placebo contrast, rather than for a single four-group test. Smaller effects require more participants to detect with the same power target, which is why planning for 75% or 50% of an observed effect leads to larger per-arm requirements than planning for the full observed effect. Such illustrations are sensitive to the observed effect and should not be mistaken for a prospective justification for 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 = 0.197; pooled standard deviation σ = 1.983.
2. n = 2 × (1.96 + 0.842)² × 1.983² / 0.197² = 1,594.7, rounded up to 1,595 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 <- 0.1967                      # observed difference in means
sigma <- 1.98254419148326                     # 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(4123405)
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 = 1,595 (80% power), 2,135 (90% power)
 75% of observed effect: n per arm = 2,835 (80% power), 3,796 (90% power)
 50% of observed effect: n per arm = 6,379 (80% power), 8,540 (90% power)
power.t.test: 1595.6 
Simulated power at n = 1,595 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.

13. Multiplicity, Missing Data and Analysis Populations

The primary outcome is one of multiple outcomes recorded for the trial. The registry lists secondary outcomes covering time to onset of action, MSS development over the study, and SNOT-22 by visit and change from baseline, with Full Analysis Set and per-protocol versions among the listed analyses. The posted record indicates 12 outcome measures and 10 secondary outcomes posted. The primary endpoint result discussed in the record is the Full Analysis Set MSS change.

When several outcomes, time points, or treatment comparisons are tested, the chance of at least one small p-value can increase. In general, multiplicity procedures can control that risk, while a prespecified hierarchy can distinguish primary from secondary questions. The registry record does not report whether multiplicity was controlled, how the three acetylcysteine-versus-placebo comparisons were treated in the original analysis, or whether an outcome hierarchy was used. The recalculated p-values are unadjusted and should not be treated as if they account for the number of comparisons.

The registry defines the Full Analysis Set as randomized patients who received at least one dose and had at least one post-baseline MSS assessment during double-blind treatment. It also identifies per-protocol versions of some secondary outcomes. The inclusion criteria for the per-protocol set, the number of patients in that set, and how departures from protocol were handled are not reported in the registry record. A specific missing-data method, imputation approach, or sensitivity analysis for missing MSS observations is also not reported.

These omissions limit assessment of how robust the primary comparison is to analysis choices and missing observations. They do not change the arithmetic of the posted group summaries, but they mean the summaries cannot establish whether the original analysis accounted for repeated measurements, baseline values, missingness, or multiplicity in a particular way. The registry record also does not report a statistical analysis plan that would clarify which analyses were prespecified.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: concussion (0.4%), hand fracture (0.4%), tibia fracture (0.4%), subarachnoid haemorrhage (0.4%).

The serious adverse event figures are reported by group. The registry lists zero affected participants among 235 at risk in the 600 mg acetylcysteine group, zero among 238 in the 1200 mg group, zero among 238 in the 2400 mg group, and one among 233 in the placebo group. Deaths are listed as zero in all four groups. These are descriptive counts; they do not establish that serious events are impossible or that group risks differ.

For other adverse events, the registry lists 9 affected participants in the 600 mg group, 15 in the 1200 mg group, 15 in the 2400 mg group, and 8 in the placebo group. The record also names Concussion, Hand fracture, Tibia fracture, and Subarachnoid haemorrhage among serious-event terms, with 0.4% listed for each. These terms are not assigned to particular groups in the posted information, so group attribution should not be inferred.

In general, adverse-event counts are descriptive unless the record also provides a defined comparative analysis and sufficient detail on ascertainment and follow-up. The registry record does not report confidence intervals or a statistical comparison for these safety counts. The counts should therefore be read as recorded events in the listed groups, not as a definitive comparison of safety between treatments.

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

The posted primary results describe average MSS changes during treatment in four groups. All four group means show negative change from baseline, and the acetylcysteine-versus-placebo mean-difference estimates are positive. Given the score definition, this means the acetylcysteine groups had less negative average changes than placebo in these unadjusted summaries. The confidence intervals include zero for all three comparisons, so the estimates are not precise enough to rule out no mean difference or differences in either direction.

This is a statistical description of the recorded endpoint, not a conclusion about whether acetylcysteine does or does not work. The trial’s MSS measure combines five symptoms and averages change from Day 2 through Day 15. That result does not by itself describe every symptom separately, the time course on each day, or outcomes beyond the recorded follow-up period. The registry lists time to onset, MSS development, and SNOT-22 outcomes as secondary measures, but their numerical results are not reported in the record.

The record does not report a clinical-importance threshold for the MSS, so statistical estimates cannot be translated into a judgment about whether a difference would matter to patients. Nor does the information establish that the three doses have equivalent effects: intervals that include zero indicate uncertainty, not proof of equivalence. The comparisons are unadjusted recalculations from group-level summaries, and details of the original analysis, missing-data handling, and multiplicity control are not reported in the registry record.

Likewise, the descriptive adverse-event counts should not be read as a complete assessment of comparative safety. The counts give the reported number of affected participants in each group, but the registry record does not provide a statistical safety comparison or uncertainty estimates for those counts. The most defensible interpretation is therefore bounded: the record reports similar-scale mean MSS changes across groups, with imprecise unadjusted contrasts, and descriptive event counts that do not alone establish comparative safety.

16. Why This Trial Matters Statistically

This trial is statistically informative because its primary question involves three active dose groups compared with a shared placebo group. The multiple comparisons make it important to distinguish an individual unadjusted contrast from a prespecified overall testing strategy. The registry record gives the three unadjusted recalculated contrasts and confidence intervals, but does not report a multiplicity method or original analysis plan. That distinction matters when readers interpret p-values across dose comparisons and a broader set of outcomes.

The endpoint also illustrates how a continuous composite score can summarize several symptoms over repeated days. The MSS is defined from five symptom ratings, and the primary summary averages change during Day 2 to Day 15 relative to Day 1. This provides an interpretable overall score change, but average change alone can conceal variation among symptoms and time points. The record lists additional time-course and patient-reported outcomes, but does not report their numerical results in this primary result information.

Finally, the confidence intervals make precision central to interpretation. Each estimated contrast is compatible with zero and with values on either side of zero. That leaves uncertainty about direction and magnitude even though the arm means are precisely stated to three decimal places. Reporting effect estimates alongside uncertainty is more informative than relying on p-values alone, while the absence of a registry-reported clinical-importance threshold limits judgments about practical meaning. Together, these features show why endpoint definition, analysis population, multiplicity, missing data, and precision all matter when reading a clinical-trial result.

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.

Several trial-specific details needed for a full statistical appraisal are not reported in the registry record. These include the original sample-size justification, the statistical analysis plan, the method for random sequence generation and allocation concealment, the exact masking procedures, and any covariate-adjusted or repeated-measures model used for the primary endpoint. The planning illustrations based on observed effects do not supply the trial’s original design rationale.

The primary endpoint is described clearly as an average change in MSS, but a clinically important difference threshold is not reported. The registry record also does not report participant-level score distributions, changes for individual symptoms, or numerical results for the listed secondary outcomes. Consequently, the posted primary summaries cannot establish how the daily course varied or whether the composite score’s components moved in similar ways.

The Full Analysis Set definition requires at least one post-baseline assessment, so participants without such an assessment are not part of that defined set. The registry record does not give the number or reasons for missing observations, explain the difference between enrollment and the analysis group counts, or describe imputation and sensitivity analyses. It also does not report the per-protocol population size or its criteria.

The three contrast estimates are unadjusted recalculations from summary statistics. The record does not provide an adjusted sponsor estimate for comparison, multiplicity control, or confidence intervals for the safety counts. These limitations do not invalidate the posted figures, but they constrain how broadly they can be interpreted and how directly they can be compared with a full prespecified analysis.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Safety of Acetylcysteine for the Treatment of Acute Uncomplicated Rhinosinusitis — NCT04123405.
• Registry record last updated 2021-11-19; status last verified 2021-10.
• Results first posted 2021-11-19.
• 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 describes NCT04123405, a completed, phase 3, randomized, double-blind, parallel-group trial of acetylcysteine for acute uncomplicated rhinosinusitis. Listed enrollment was 944. Participants were assigned to 600 mg, 1200 mg, or 2400 mg acetylcysteine, or placebo. The primary outcome was mean change from baseline in daily MSS over Day 2 to Day 15 in the Full Analysis Set.

Mean changes were -4.821, -4.739, -4.776, and -5.018, respectively. The unadjusted recalculated mean differences versus placebo were 0.197, 0.279, and 0.242; all three confidence intervals included zero. The record also reports descriptive adverse-event counts and identifies several unassigned serious-event terms. Details of the original statistical plan, multiplicity handling, and missing-data methods are not reported in the registry record.