A Clinical Trial to Compare the Efficacy and Safety of 1-week Treatment of Intravenous N-acetylcysteine (NAC) 600 mg Twice Daily, Ambroxol Hydrochloride 30 mg Twice Daily and Placebo as Expectorant Therapies in Adult Chinese Patients With Respiratory Tract Diseases and Abnormal Mucus Secretions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Trial to Compare the Efficacy and Safety of 1-week Treatment of Intravenous N-acetylcysteine (NAC) 600 mg Twice Daily, Ambroxol Hydrochloride 30 mg Twice Daily and Placebo as Expectorant Therapies in Adult Chinese Patients With Respiratory Tract Diseases and Abnormal Mucus Secretions (NCT03843541), a randomized phase 3 study. The primary outcome is Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo.

2. Clinical Question

The endpoint uses a four-point ordinal scale, where 0 represents liquid sputum with normal viscosity and 3 represents sticky sputum with severely increased viscosity. Lower scores correspond to less viscosity on this scale. The registry reports mean changes, while the scale itself consists of ordered categories rather than measurements with necessarily equal intervals.

The trial’s wider clinical question also includes comparisons of expectoration difficulty, sputum color and volume, and cough severity at specified follow-up times. Those outcomes help describe other aspects of mucus-related symptoms, but they are distinct from the primary question about sputum viscosity. The registry record does not report a broader clinical outcome that would establish how these score changes translate into a patient’s overall experience.

3. Trial Design

This was a Phase III, randomized, double-blind, parallel-group trial with placebo and active control. The record describes masking of both raters and patients. Participants were assigned to NAC, ambroxol hydrochloride, or placebo, with a planned allocation ratio of 1:1:1. The study was conducted in China and was sponsored by Zambon SpA.

The registry lists an enrollment of 333. Its brief summary describes an approximately 8-month study, including an enrolment period of approximately 7 months and patient participation lasting 1 month or 4 weeks. For each patient, the described schedule included screening of up to 1 week, a 1-week treatment period, and a 2-week follow-up period. The summary anticipated approximately 15-25 sites in China. These are descriptions of the planned design; they do not by themselves establish how every participant proceeded through the study.

The primary outcome was change from baseline to Day 7 in mean sputum-viscosity score for NAC and placebo. The registry identifies the analysis population as mITT and defines it as participants in the ITT population who received at least one dose or partial dose of the investigational medicinal product. The arm-level outcome data list 108 participants for NAC and 110 for placebo. The registry record does not report why these outcome counts differ from the overall enrollment or provide a complete account of exclusions and missing measurements.

Other listed outcomes cover changes in sputum viscosity, expectoration difficulty, sputum color, cough severity, and sputum volume at Day 3 or Day 7, and include comparisons involving ambroxol. The record lists 15 outcome measures and 22 analyses, while 12 secondary outcomes are posted. The trial status is completed. Details of the original sample-size justification, interim analyses, and the full prespecified statistical plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Participants who met the inclusion and none of the exclusion criteria were enrolled to the study. All procedures were performed as per the trial flow chart.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: mITT population - The Modified ITT (mITT) Population comprised all participants in the ITT population who received at least 1 dose or partial dose of the IMP.

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: mITT population - The Modified ITT (mITT) Population comprised all participants in the ITT population who received at least 1 dose or partial dose of the Investigational Medicinal Product (IMP).

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline to Day 7 of Mean Sputum Viscosity Score of NAC and Placebo, measured over From baseline upto Day 7.

The primary endpoint is the change from baseline to Day 7 in mean sputum-viscosity score, comparing NAC with placebo. Sputum viscosity was assessed using an ordinal four-point scale: 0 is liquid with normal viscosity, 1 is fluid with mildly increased viscosity, 2 is viscous with moderately increased viscosity, and 3 is sticky with severely increased viscosity. Zero is the best score and 3 the worst. A change score describes how the recorded score differs from its baseline value over the specified period; a negative change indicates movement toward a lower score on this scale.

Sputum viscosity is used as an outcome because it directly measures one of the mucus characteristics targeted by the trial’s expectorant-therapy question. It is not a direct measure of every symptom or of overall health. Other outcomes in the registry address expectoration difficulty, sputum color and volume, and cough severity, providing distinct measures of the respiratory symptoms under study.

There is an important measurement distinction: the scale has ordered categories, while the posted outcome is described as a mean and standard deviation. Means can offer a compact summary of group scores, but interpreting a mean difference as though each step on the scale represents an identical amount of change requires caution. The sponsor’s reported primary comparison uses a Wilcoxon (Mann-Whitney) method, which is rank-based rather than a direct comparison of means.

The primary endpoint therefore gives evidence about the distribution of the recorded sputum-viscosity scores at the specified follow-up, interpreted alongside the analysis method. It does not, on its own, settle the results for the other outcomes or establish the importance of a score change to patients.

7. Results Posted in the Registry

• N-Acetylcysteine: mean -1.20 versus -1.00 on control; difference -0.20 (95% CI -0.40 to 0.00), standardized effect d = -0.26; z-test p = 0.052.

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.

Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo

• 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:
  • N-Acetylcysteine: mean -0.60 versus -0.60 on control; difference 0.00 (95% CI -0.16 to 0.16), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between N-Acetylcysteine and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo

• 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:
  • N-Acetylcysteine: mean -0.80 versus -0.70 on control; difference -0.10 (95% CI -0.27 to 0.07), standardized effect d = -0.16; z-test p = 0.238.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between N-Acetylcysteine and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride

• 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:
  • Ambroxol Hydrochloride: mean -1.20 versus -1.20 on control; difference 0.00 (95% CI -0.20 to 0.20), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ambroxol Hydrochloride and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend beyond the primary sputum-viscosity comparison to expectoration difficulty, sputum color, cough severity, and sputum volume. They include assessments at Day 3 and Day 7 and comparisons involving NAC, placebo, and ambroxol. This breadth provides a wider picture of the measured symptom domains, but it also means that the secondary findings are not a single independent confirmation of the primary result.

Across the posted secondary results, the pattern is not uniform: the reported analyses include results with different p-values, and some summary-statistic recalculations do not align with the sponsor’s reported tests. This means that the secondary outcomes should be interpreted as a collection of distinct comparisons, not collapsed into a simple statement that every outcome points in the same direction. The registry record lists 15 outcome measures and 22 analyses, with 12 secondary outcomes posted.

These results relate to the primary endpoint by addressing other related measures and follow-up times. They can add context about whether the primary result is accompanied by changes in other recorded aspects of respiratory symptoms. They do not change the definition of the primary endpoint, and do not by themselves establish that the primary comparison is robust across all measures.

Unadjusted secondary p-values carry less weight because testing multiple outcomes and time points increases the chance of obtaining a nominally small p-value by chance. A multiplicity procedure can account for that family of tests, but such a procedure is not reported in the registry record. Without that information, individual secondary results are best treated as supportive or exploratory rather than as stand-alone confirmatory findings. The discrepancy between certain reported analyses and recalculations further reinforces the need to avoid overinterpreting isolated results.

The secondary findings therefore help characterize the range of outcomes assessed, but they should be read in the context of their multiplicity, analysis methods, and incomplete reporting. They are not a substitute for the sponsor’s primary analysis or an independent demonstration that the primary contrast has the same interpretation across all endpoints.

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

• Change From Baseline to Day 3 in Mean Sputum Viscosity Score of NAC and Placebo
• Change From Baseline to Day 3 in Mean Expectoration Difficulty Score of NAC and Placebo
• Change From Baseline to Day 3 and to Day 7 in Mean Sputum Color Score of NAC and Placebo
• Change From Baseline to Day 3 and to Day 7 in Mean Cough Severity Score of NAC and Placebo
• Change From Baseline to Day 3 and to Day 7 of Mean Sputum Volume of NAC and Placebo
• Change From Baseline to Day 7 in Mean Sputum Viscosity Score of NAC and Ambroxol Hydrochloride
• Change From Baseline to Day 7 in Mean Expectoration Difficulty Score of NAC and Ambroxol Hydrochloride
• Change From Baseline to Day 3 and to Day 7 in Mean Sputum Viscosity Score of Ambroxol Hydrochloride and Placebo

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is a score recorded on an ordinal scale, but the registry also reports group means and standard deviations. The sponsor’s posted primary analysis uses the Wilcoxon (Mann-Whitney) method. The recalculation uses only the posted summary statistics to make a simple, unadjusted comparison of means. These methods summarize and test the data differently, so their estimates, uncertainty measures, and p-values need not match.

What does the mean difference describe?

A mean is the arithmetic average of recorded values. The posted mean change for each arm describes the average change from baseline to Day 7 in that arm. The recalculated mean difference compares those two averages. Its estimate of -0.2 is the NAC mean change relative to the placebo mean change as expressed in the posted summaries. The sign reflects the ordering of the comparison; the scale’s lower scores represent less viscosity.

A mean difference is easy to read as a contrast between average scores, but an ordinal scale does not guarantee that the distance between adjacent categories is uniform. For that reason, the mean-based recalculation is a useful descriptive check, not necessarily the most suitable summary of every feature of the score distribution. The sponsor’s rank-based method uses the ordering of observations and does not require treating the scale’s steps as equal intervals in the same way.

What does the Wilcoxon (Mann-Whitney) method do?

In general, a rank-based comparison orders the observations and evaluates whether values in one group tend to be higher or lower than values in the other group. It is not simply a test of the difference between the two arithmetic means. Its interpretation depends on the distributional pattern and the parameter reported. The registry reports a net mean difference for the primary comparison, but does not provide a confidence interval or further detail sufficient to reconstruct how that reported parameter was obtained.

The sponsor’s primary p-value is p < 0.001. A p-value measures how unusual the data, or data at least as inconsistent with the null hypothesis, would be under the null and the analysis assumptions. It is not the probability that the null is true, a measure of effect size, or a measure of clinical relevance. It also does not show how precisely the estimated difference is known; that is usually assessed using a confidence interval.

Why can the recalculation differ?

The recalculation is explicitly unadjusted and based on summary means, standard deviations, and arm counts. It does not have access to participant-level observations, covariates, ranks, or other details that may enter the sponsor’s analysis. A test based on ranks and a comparison based on means can produce different results, especially when the outcome is ordinal or its distribution is not well represented by a mean and standard deviation. The registry record does not report enough detail to attribute the discrepancy to a particular feature of the analysis.

For the primary outcome, the recalculated mean difference is -0.2 and its 95% confidence interval is -0.402 to 0.002. The interval describes uncertainty for that simple mean-based comparison under its assumptions. It is not the confidence interval for the sponsor’s Wilcoxon result. Since the record marks the discrepancy, the sponsor’s own analysis takes precedence for the trial’s reported primary conclusion, while the recalculation remains a transparent check on the posted summary values.

How should secondary p-values be read?

For secondary outcomes, the registry posts a mixture of rank-based methods and comparisons whose posted means can also be recalculated. The reported Day 3 analysis of expectoration difficulty has p = 0.037, whereas the simple unadjusted summary-statistic recalculation has p = 0.238. The discrepancy reinforces that the recalculation and reported analysis answer different statistical questions or use different information. The sponsor’s own analysis takes precedence when they conflict.

Multiple outcomes and time points create multiple opportunities to observe a small p-value even when there is no underlying difference. Unless an appropriate multiplicity strategy is specified and applied, an isolated secondary p-value should be treated as exploratory rather than as confirmatory evidence. The registry record does not report a multiplicity adjustment or enough detail to establish how the family of secondary comparisons was handled.

What does a confidence interval add?

A confidence interval gives a range of estimates compatible with the observed data under the method used and its assumptions. Its width indicates precision: a narrower interval gives a more concentrated range, while a wider interval allows a broader range of effects. The recalculated primary interval crosses zero, but that statement applies only to the recalculated mean difference. It should not be transferred to the rank-based result.

Standard deviations describe spread among observations, while standard errors describe uncertainty in an estimated summary. Neither is a substitute for a confidence interval around the specific estimand of interest. The posted arm standard deviations and the recalculated standard errors help describe the summary-statistic analysis, but they do not provide the missing precision measure for the sponsor’s primary analysis.

What analysis details remain unclear?

The registry defines the mITT population for the primary outcome, but does not report the handling of missing endpoint data, the original sample-size justification, interim analyses, or a complete prespecified statistical plan. It also does not report whether the primary test used any further adjustments. Those details can affect interpretation and reproducibility. The posted results should therefore be read with their stated population and methods in mind, without assuming unreported procedures.

11. Confidence Intervals and Precision

For the recalculated primary mean difference, the 95% confidence interval is -0.402 to 0.002. It is centered around the estimated contrast and includes zero. This means the posted summary statistics do not rule out no mean difference under this unadjusted calculation; they also allow values on either side of zero within the interval. The interval is not a range that contains the true effect with a probability of 95% after the data have been observed. Rather, under repeated use of the method and its assumptions, intervals constructed in this way would cover the target parameter at the stated rate.

Precision concerns how narrowly an estimate is determined. A confidence interval gives more information about precision than a p-value alone because it displays a range of values compatible with the analysis. The recalculated interval is tied to the mean-difference estimand and the assumptions used in the simple comparison. It does not quantify uncertainty for the sponsor’s rank-based analysis.

The registry does not report a confidence interval for the sponsor’s primary result. Thus the sponsor’s p < 0.001 can be cited as the reported test result, but the posted record does not allow the reader to assess the precision of the sponsor’s estimated parameter by an accompanying interval. The reported value of -0.24 is not accompanied by interval bounds in the record.

Because the endpoint is ordinal and summarized as a mean, interpretation of the recalculated interval also depends on treating the posted means and standard deviations as suitable inputs to that comparison. It should be viewed as a simple unadjusted re-calculation, not as a substitute for the trial’s planned analysis or an interval for an ordinal rank-based estimand. The difference between the two analyses is a central limitation in judging precision from registry results.

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 illustrations based on the observed effect, not a description of the trial’s original design calculations. For this continuous endpoint, the listed quantities are participants per arm, not a total across arms or a count of events. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect used for each planning scenario is the stated fraction of the observed effect.

The 80% power column gives the estimated participants per arm for a design with an 80% chance of detecting the specified effect if that effect is real and the planning assumptions hold. The 90% power column gives the corresponding per-arm planning count for a 90% chance under those assumptions. Greater planned power generally requires a larger sample for the same effect. These figures are not observed power: they are prospective planning illustrations and do not measure the probability that the completed trial detected an effect.

The rows consider planning for 100%, 75%, and 50% of the observed effect. The smaller the effect one aims to detect, the more participants are needed, because a smaller separation between groups is harder to distinguish from sampling variability. In the displayed scenarios, the required per-arm counts rise as the assumed target effect becomes a smaller fraction of the observed effect. This pattern is a general feature of statistical planning, not evidence that any one of those effects is the true effect.

The original sample-size justification and the assumptions actually used to design the trial are not reported in the registry record. Therefore, these planning counts should not be used to infer whether the completed trial was adequately sized according to its original protocol. They are conditional illustrations based on the observed estimate and the stated planning assumptions, and should be interpreted alongside the uncertainty and discrepancy in the primary result.

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 = -0.200; pooled standard deviation σ = 0.760.
2. n = 2 × (1.96 + 0.842)² × 0.760² / -0.200² = 226.9, rounded up to 227 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 <- -0.2                      # observed difference in means
sigma <- 0.76044821091346                     # 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(3843541)
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 = 227 (80% power), 304 (90% power)
 75% of observed effect: n per arm = 404 (80% power), 541 (90% power)
 50% of observed effect: n per arm = 908 (80% power), 1,216 (90% power)
power.t.test: 227.9 
Simulated power at n = 227 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.

14. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis compares NAC with placebo using a Wilcoxon (Mann-Whitney) method. It reports a net mean difference of -0.24 and p < 0.001, with a superiority analysis type. The registry does not provide confidence limits for that primary reported value.

The recalculation is a separate, simple unadjusted comparison of the posted arm means and standard deviations. It estimates a mean difference of -0.2, with a 95% confidence interval from -0.402 to 0.002 and p = 0.052. That result does not match the sponsor’s reported analysis. The difference is not resolved by treating one p-value as a correction of the other: the methods and the quantities being compared are not identical, and the registry does not include enough participant-level or analysis detail to reproduce the sponsor’s result.

The record flags a discrepancy, so the sponsor’s own analysis takes precedence as the trial’s reported primary analysis. That precedence is not a claim that the analysis is free of limitations. It remains important to note that the posted confidence interval belongs to the recalculated mean difference, not the sponsor’s rank-based analysis. Readers should keep the reported trial result and the independent summary-statistic check distinct.

The same caution applies to secondary results where sponsor analyses and simple recalculations diverge. A recalculated p-value is not a replacement for a prespecified trial analysis. Conversely, reporting the sponsor’s result does not remove the need to consider whether the method, endpoint scale, population, and missing-data handling are sufficiently described in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures, 22 analyses, and 12 posted secondary outcomes. Several outcomes are assessed at more than one follow-up time or compare different groups. When many hypotheses are tested, the chance of encountering a nominally small p-value somewhere among them is higher than for a single prespecified test. Multiplicity methods can control the error rate across a defined family of comparisons, but the registry record does not report whether an adjustment was planned or applied, or how the testing family was defined.

The primary analysis is identified as a superiority comparison, and the primary outcome and time point are specified. However, the original sample-size justification and full prespecified statistical plan are not reported in the registry record. The record also does not report whether interim analyses were conducted. Those omissions limit assessment of whether the reported analysis followed a prospectively specified plan and whether any planned decision rules affected interpretation.

The registry defines the mITT population as participants in the ITT population who received at least one dose or partial dose of the investigational medicinal product. It does not provide a complete description of the analysis populations for every endpoint, nor does it report how missing Day 3 or Day 7 measurements were handled. Missing-data methods matter because the analysis can depend on how many outcome values are unavailable and whether the missingness is related to participants’ outcomes or study experience. The posted record does not provide enough detail to assess those possibilities.

The arm-level primary outcome counts are 108 for NAC and 110 for placebo, while the overall registry enrollment is 333. The record does not explain the difference between the total enrollment and these outcome counts, so no reason for that difference should be inferred. Nor does it give enough detail to determine whether all randomized participants were included in each posted analysis.

These reporting gaps do not establish that a particular procedure was or was not used. They define what cannot be evaluated from the registry record: multiplicity control, missing-data handling, interim-analysis procedures, the original sample-size rationale, and the full analysis plan. This uncertainty is especially relevant when interpreting secondary p-values and discrepancies between the sponsor’s analyses and summary-statistic recalculations.

16. 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: chronic obstructive pulmonary disease (1.8%), cardiac failure (0.9%), non-small lung cancer (0.9%), arteriosclerosis coronary artery (0.9%), anti-neutrophil cytoplasmic antibody positive vasculitis (0.9%).

The registry posts serious adverse event counts by arm: 2 participants in the NAC group, 5 in the ambroxol hydrochloride group, and 7 in the placebo group. The respective numbers at risk are 108, 110, and 110. These are counts of participants with serious adverse events, not a measure of the severity or causality of every event and not a comparison adjusted for differences between participants.

The record also lists deaths: 1 in the NAC group and 0 in each of the ambroxol hydrochloride and placebo groups. The registry counts alone do not establish whether an event or death was caused by a study treatment. The posted serious-event terms include chronic obstructive pulmonary disease, cardiac failure, non-small lung cancer, arteriosclerosis coronary artery, anti-neutrophil cytoplasmic antibody positive vasculitis, and hemoptysis. Their inclusion in a registry listing does not establish a causal relationship to an intervention.

These figures are descriptive safety information for the reported groups. A fuller assessment would require details such as event timing, severity, relatedness assessment, follow-up completeness, and the definitions used for reporting. Those details are not reported in the registry record in the registry record for these results. The counts should therefore be read as posted event totals, not as proof of comparative safety or risk.

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

The registry reports a primary superiority analysis comparing NAC with placebo for change in sputum-viscosity score from baseline to Day 7. The sponsor’s rank-based analysis reports a net mean difference of -0.24 and p < 0.001. The posted arm means show negative mean changes in both groups. Taken together, these registry entries describe the reported statistical result and the direction of the group summaries on a scale where lower scores represent less viscosity.

They do not establish that every participant had a lower score, that all dimensions of respiratory symptoms changed similarly, or that the measured difference has a particular importance to patients. A group summary does not describe every individual outcome. The registry record does not report a threshold for a clinically important difference or a direct interpretation of the score change in terms of patients’ daily experience.

The sponsor’s reported analysis and the unadjusted recalculation from summary statistics disagree. The recalculated mean-difference interval includes zero, but it is not an interval for the sponsor’s rank-based result. The sponsor’s own analysis takes precedence for the reported trial conclusion, while the disagreement limits how confidently the two sets of posted statistics can be reconciled. The registry lacks a confidence interval for the sponsor’s primary result, so the precision of that reported estimate cannot be assessed from an interval in the record.

The study also assessed other outcomes and included an ambroxol active-control arm. Secondary endpoints may provide context, but their multiplicity, differing methods, and some discrepancies make isolated secondary findings less conclusive. The available record does not justify extending the primary result to every secondary symptom or comparison.

Finally, a registry result is not the same as a full report of all protocol and analysis details. The record does not report the original sample-size justification, interim analyses, multiplicity procedures, or missing-data methods. Those gaps mean that the posted results can describe the registered analyses, but cannot answer every question about the trial’s conduct, robustness, or clinical meaning.

18. Why This Trial Matters Statistically

This trial illustrates why the statistical method and the outcome scale both matter. Sputum viscosity was recorded on an ordinal four-point scale, while the posted descriptive summaries are means and standard deviations. The sponsor used a rank-based primary analysis, whereas a simple recalculation from the summary statistics compares means. Each approach summarizes the data differently, and the discrepancy in their conclusions makes it especially important to name the estimand and method rather than presenting a p-value without context.

The registry also makes a useful distinction between a sponsor-reported analysis and a transparent recalculation. The recalculated estimate and interval show what follows from the posted summary statistics under a straightforward unadjusted comparison. They do not reproduce the sponsor’s test. For clinical researchers and statisticians, keeping these analyses separate is essential: an independently calculated check can illuminate a record without superseding the trial’s own analysis.

The endpoint set illustrates the challenge of multiple outcome domains and follow-up times. The primary result is one prespecified comparison, while secondary findings span other symptoms and contrasts. Without reported multiplicity procedures, nominal secondary p-values should not be treated as a series of confirmatory tests. Incomplete reporting of missing-data methods and the original sample-size rationale also constrains evaluation of robustness and design decisions.

Finally, the safety counts emphasize the difference between descriptive event reporting and causal inference. Counts across groups are informative as a registry record, but they do not on their own show that treatment caused an event or establish comparative safety. Taken together, these features make the trial a useful example of how conclusions depend not only on numerical results, but also on measurement, analysis choices, uncertainty, and reporting completeness.

19. 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.

A key limitation is the mismatch between the sponsor’s reported primary result and the simple recalculation from posted means and standard deviations. The record flags a discrepancy, but does not provide enough detail to reproduce the sponsor’s rank-based analysis or explain the difference. The sponsor’s analysis takes precedence as the trial’s reported result, but the discrepancy remains relevant to interpretation.

The primary scale is ordinal, yet the outcome is summarized using means and standard deviations. Those summaries may not convey the full distribution of scores or the pattern of changes across categories. The sponsor’s primary rank-based method accounts for ordering, but the record does not include a confidence interval for that reported result. The recalculated interval applies to a different mean-based analysis and cannot fill that gap.

Important statistical details are not reported in the registry record: the original sample-size justification, full prespecified statistical plan, interim analyses, multiplicity handling, and missing-data methods. The record also does not explain the difference between overall enrollment of 333 and the outcome counts of 108 for NAC and 110 for placebo. This prevents a full assessment of analysis-population flow and endpoint completeness.

The registry lists a broad set of secondary outcomes and analyses. Without a reported strategy for handling multiple comparisons, individual secondary p-values are vulnerable to overinterpretation. Some sponsor analyses also differ from simple recalculations, so the secondary findings should not be treated as a uniformly consistent body of evidence.

For safety, the registry provides serious adverse event and death counts but not enough detail to assess timing, relatedness, or completeness of follow-up. The counts are descriptive and do not determine causality. In addition, the posted result set does not by itself provide the fuller clinical context needed to judge the importance of score changes to patients.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Clinical Trial to Compare the Efficacy and Safety of 1-week Treatment of Intravenous N-acetylcysteine (NAC) 600 mg Twice Daily, Ambroxol Hydrochloride 30 mg Twice Daily and Placebo as Expectorant Therapies in Adult Chinese Patients With Respiratory Tract Diseases and Abnormal Mucus Secretions — NCT03843541.
• Registry record last updated 2025-09-05; status last verified 2025-09.
• Results first posted 2023-01-05.
• 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.

23. Record Summary

NCT03843541 is a completed Phase III randomized, double-blind, parallel-group trial sponsored by Zambon SpA. It compared 1-week intravenous treatment with NAC, ambroxol hydrochloride, or placebo in adult Chinese patients with respiratory tract diseases and abnormal mucus secretions.

The primary outcome was change from baseline to Day 7 in mean sputum-viscosity score, comparing NAC with placebo in the mITT population. The sponsor reported a Wilcoxon (Mann-Whitney) analysis with a net mean difference of -0.24 and p < 0.001. A simple unadjusted mean-based recalculation gives a difference of -0.2 and a 95% confidence interval from -0.402 to 0.002. The registry flags this discrepancy, so the sponsor’s own analysis takes precedence.

The record also posts secondary outcomes and safety counts, but does not report key details including multiplicity procedures, missing-data handling, the original sample-size justification, or the full prespecified statistical plan. Those gaps, along with the difference between the primary analyses, limit how fully the results can be evaluated from the registry record alone.