A Safety and Efficacy Study of NAC in Patients With TA-TMA: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Efficacy Study of NAC in Patients With TA-TMA (NCT03252925), a randomized phase 3 study. The primary outcome is The Incidence of TA-TMA..

2. Clinical Question

The trial record describes the study as evaluating NAC safety and efficacy in patients with TA-TMA. Its primary endpoint is an event count: participants recorded as having TA-TMA after HSCT. The posted result gives five events in the NAC group and fifteen in the placebo group. Those counts are accompanied by group sizes of 66 and 77, respectively. They describe the posted outcome, but do not by themselves explain the clinical characteristics of the participants or how TA-TMA was diagnosed and assessed.

The clinical question is specific to this trial population and its 100-day outcome period. The registry does not report enough eligibility detail to determine how broadly the participants represent other transplant populations, nor does it provide treatment details needed to reproduce the NAC regimen. The comparison therefore concerns the registered groups and endpoint, rather than every possible use of NAC or every clinical setting involving TA-TMA.

3. Trial Design

The registry identifies this as a Phase 3 randomized, double-masked, parallel study of N-acetylcysteine and placebo oral tablets. The listed enrollment is 170. The record is marked completed and identifies The First Affiliated Hospital of Soochow University as the sponsor. The listed study start is 2017-11-01, and primary completion is listed as 2021-10-01.

The primary outcome is the incidence of TA-TMA after HSCT, expressed as the number of participants with the event over a 100-day timeframe. In the posted outcome groups, the NAC arm has 66 participants and five events; the placebo arm has 77 participants and fifteen events. The registry does not explain how the posted endpoint group sizes relate to the enrollment figure, and it does not report the analysis population definition or the handling of participants with incomplete outcome information.

Four secondary outcomes are named: levels of VWF multimers, endothelial micro particles, TNF-α, and ROS. Numeric results for those measures are not included in the registry record for this account. The registry lists five outcome measures in total, including the primary outcome, and zero analysis records. Consequently, the posted primary comparison can be described, but details such as model specification, covariate adjustment, subgroup analyses, and multiplicity procedures are not reported in the registry record.

Randomization and masking are design features intended to reduce systematic differences and knowledge-related influence during a trial. The record does not give the sequence-generation method, allocation concealment details, which study roles were masked, or whether masking was maintained. It also does not state the original sample-size assumptions or the planned statistical analysis. Those omissions limit how fully the conduct and analysis can be reconstructed from the registry record alone.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this 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 The Incidence of TA-TMA., measured over 100 days.

The primary endpoint is the incidence of TA-TMA after HSCT, measured as the count of participants who experienced the event during the 100-day timeframe. The record labels the unit as participants and describes the outcome as the incidence of TMA after HSCT. The posted counts are five participants in the NAC group and fifteen in the placebo group.

A participant-level event endpoint gives a direct count of how many people had the outcome during the specified period. Comparing event counts in relation to the number of participants in each group can describe the observed difference between the randomized arms. In general, an incidence endpoint is useful when the research question concerns whether an event occurred during a defined follow-up window. It does not, by itself, describe the timing of each event, its severity, or how long participants remained at risk.

The record does not provide a detailed diagnostic definition for TA-TMA, rules for adjudicating events, or information about the timing of outcome assessments. It also does not report the analysis population or how missing endpoint information was handled. Those details matter when interpreting what qualified as an event and whether all randomized participants contributed to the posted comparison. The endpoint should therefore be read as the registry’s reported participant count within its stated 100-day timeframe, without assuming additional outcome-assessment procedures.

7. Results Posted in the Registry

• NAC Group: 7.6% (5/66) versus 19.5% (15/77) on control; risk difference -11.9 percentage points (95% CI -22.8 to -1.0), risk ratio 0.39 (0.15–1.01); unadjusted two-proportion z-test p = 0.041.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary outcome count?

The primary outcome is binary at the participant level: a participant is counted as having TA-TMA during the stated 100-day timeframe or is not counted as having the event. The registry reports event counts and group sizes for the NAC and placebo arms. In general, a binary endpoint can be summarized using the proportion of participants with an event, or by comparing those proportions using an effect measure such as a risk difference. The registry comparison reports a risk difference of -0.119. A negative value, with the NAC group as the comparison arm, means that the observed event proportion is lower in that group than in the placebo group.

The risk difference is an absolute contrast in event proportions, rather than a ratio. It gives a scale for describing how far apart the observed group proportions are. It does not tell whether an observed difference is clinically important, and it can be imprecise when event counts are limited. The registry also reports the event counts and group sizes, which allow readers to see the basis of the comparison rather than relying only on a single effect estimate.

What does an unadjusted p-value mean?

The posted comparison includes an unadjusted p-value of 0.041. In general, a p-value is calculated under a null hypothesis, such as no difference between groups, and describes how unusual the observed data or more extreme data would be if that null model and the test assumptions held. It is not a measure of the probability that the null is true. It also does not express the probability that a finding will reproduce, or the size of the effect.

“Unadjusted” indicates that the posted p-value is not reported as adjusted for other covariates or for testing multiple outcomes. The registry does not specify the exact test used, the full analysis plan, or any covariate-adjustment procedure. Therefore, the p-value should be read as the unadjusted value attached to the registry comparison, not as evidence that every possible source of bias or uncertainty has been addressed.

How should the confidence interval be understood?

A confidence interval describes a range of effect estimates compatible with the observed data under a particular statistical procedure. In general, a narrower interval indicates greater precision and a wider interval indicates greater uncertainty. For a risk difference, zero is the value corresponding to no difference between groups. The posted interval for the risk difference lies below zero, with its upper end close to zero. The confidence level and interval-construction method are not reported in the registry record, so the interval should not be assigned an unreported confidence level.

An interval does not show the range of individual participant outcomes, and it is not a guarantee that the true effect lies within its endpoints. It depends on the statistical model and assumptions used to construct it. The record does not identify those details. The interval is most useful alongside the point estimate and event counts, rather than as a standalone verdict.

What do randomization and masking contribute?

Randomization assigns participants to study groups using a chance-based process. In general, random allocation can reduce systematic differences in characteristics between groups, including characteristics that are not measured, especially when the allocation process is implemented appropriately. Double masking is intended to limit the influence of treatment knowledge on participant experiences, clinical management, or outcome assessment. The registry records the study as randomized and double-masked, but it does not describe sequence generation, concealment, which roles were masked, or whether masking was maintained.

The parallel design means that participants are assigned to one study group rather than crossing between the intervention and comparator as part of the listed design. This makes the between-group comparison central to interpretation. Randomization and masking improve the design’s potential for a fair comparison, but their labels alone do not establish that the trial had no bias. Information about adherence, crossover, withdrawals, and analysis populations is not reported in the registry record.

What analysis details remain unknown?

The registry lists no analysis records. It does not report a protocol-level statistical plan, the exact test for the primary endpoint, covariate adjustment, subgroup analyses, interim analyses, or missing-data methods. These are not details that can be inferred from the event counts or the p-value. In general, analysis choices affect how estimates and uncertainty are calculated; prespecification also helps readers distinguish planned analyses from choices made after reviewing results.

Because four secondary measures are named in addition to the primary endpoint, the possibility of multiple comparisons is relevant. In general, testing several outcomes can increase the chance of at least one apparently unusual result when all null hypotheses are true. A statistical plan may address this through a defined hierarchy or adjustment procedure. Such a procedure is not reported in the registry record, and no numerical secondary-outcome results are available in the registry record for this account. No conclusion about the secondary outcomes or multiplicity-adjusted evidence can therefore be drawn.

10. Confidence Intervals and Precision

The risk-difference estimate is -0.119. Its posted confidence interval has a negative lower bound and a negative upper bound close to zero. Because the interval remains on the negative side of the null value for a risk difference, it is compatible with a lower observed event proportion in the NAC group. Its proximity to zero at the upper end also indicates that estimates close to no difference are not far from the interval boundary. The confidence level and method used to calculate the interval are not reported in the registry record.

In general, a confidence interval is a way to express the uncertainty around an estimated effect. It should not be read as a range containing a fixed proportion of individual outcomes, or as a probability statement about the true effect after the data are observed. Its width reflects the information in the data and the assumptions of the calculation. The event counts and group sizes provide important context for the estimate, while the interval communicates that the point estimate is not known without uncertainty.

The unadjusted p-value is 0.041, but it does not replace the effect estimate or its interval. A p-value addresses compatibility with a null model, whereas the estimate and interval describe the direction, scale, and precision of the observed contrast. The registry does not report a confidence level, a complete analysis plan, or adjustments for multiple outcomes. Accordingly, the interval and p-value should be interpreted as the posted unadjusted comparison, with those reporting gaps in mind.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations, not the trial’s observed group sizes. They are stated as participants per arm, not total events. The 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 set at a stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

For planning for 100% of the observed effect, the figures are 129 participants per arm for 80% power and 172 participants per arm for 90% power. For planning for 75% of the observed effect, they are 251 participants per arm for 80% power and 335 participants per arm for 90% power. For planning for 50% of the observed effect, they are 610 participants per arm for 80% power and 816 participants per arm for 90% power.

In plain terms, the 80% power column gives the estimated participants per arm needed for the assumed design to have an 80% chance of detecting the specified effect if that effect is present, under the listed assumptions. The 90% power column uses a higher target chance of detection and therefore gives larger planning figures. The curve should be read as illustrating how the required group size changes with the effect size being targeted, not as a record of what happened during the trial.

Smaller effects require more participants to detect under the same planning assumptions, which is why the figures increase when planning for a smaller fraction of the observed effect. These are planning illustrations based on the observed effect, not observed power.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.195; treatment proportion p₁ = 0.076; average p̄ = 0.135.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4837 = 0.9480.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4763 = 0.4009.
4. n = (0.9480 + 0.4009)² / (-0.1190)² = 128.4, rounded up to 129 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
p0 <- 0.194805194805195                          # control proportion
p1 <- 0.0757575757575758                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3252925)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 129 (80% power), 172 (90% power)
 75% of observed effect: n per arm = 251 (80% power), 335 (90% power)
 50% of observed effect: n per arm = 610 (80% power), 816 (90% power)
power.prop.test: 128.4 
Simulated power at n = 129 per arm: 0.812 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry names four secondary outcomes: the level of VWF multimers, the level of endothelial micro particle, the level of TNF-α, and the level of ROS. Along with the primary TA-TMA endpoint, the record lists five outcome measures. The numerical results for the secondary measures are not reported in the registry record for this account. Their timing, measurement procedures, analysis populations, and detailed definitions are also not reported in the registry record.

When a study examines more than one outcome, multiplicity can affect how evidence is interpreted. In general, testing multiple outcomes creates more opportunities for an apparently notable result to arise by chance, even if none of the underlying effects is present. Researchers may address this through a prespecified hierarchy, a multiplicity adjustment, or a clearly designated primary outcome with secondary outcomes treated as exploratory. The record identifies a primary endpoint, but does not report whether any adjustment or hierarchy was planned or used. No multiplicity-adjusted conclusions can therefore be inferred.

The registry lists zero analysis records. It does not describe the statistical plan, the exact primary test, covariates, subgroup analyses, interim analyses, or model checks. The analysis population is not defined. In particular, the record does not say whether the posted comparison uses all randomized participants, participants with observed endpoint data, or another population.

Missing-data handling is also not reported in the registry record. There is no description of missing endpoint assessments, withdrawals, exclusions, or any imputation or sensitivity analysis. The primary-outcome group sizes are 66 and 77, while the listed enrollment is 170; the registry does not explain the relationship among those figures. This gap is relevant to understanding who contributed to the endpoint comparison, but it does not establish that any particular participants were excluded or that missing data occurred. Without analysis-population and missing-data details, the posted estimates cannot be independently interpreted as an intention-to-treat or per-protocol analysis.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The posted safety figures report zero serious adverse events among 66 participants at risk in the NAC group and zero among 74 participants at risk in the placebo group. Other adverse events are reported for 59 of 66 at risk in the NAC group and 72 of 74 at risk in the placebo group. Deaths are listed for 16 in the NAC group and 27 in the placebo group. These are counts as recorded, not adjusted comparisons.

The safety denominators differ between groups and from the primary endpoint group sizes. The registry does not explain the difference, define the safety analysis population, state the observation period for these safety counts, or provide the criteria used to classify serious and other adverse events. It also does not report the serious adverse event terms in the available record. The listed death counts may overlap with adverse-event counts; the record does not clarify how outcomes relate to one another.

These figures should be read as descriptive safety reporting, not as evidence that an intervention caused or prevented an event. Without timing, event definitions, participant-level attribution, and a stated analysis approach, the counts cannot establish comparative safety or explain why events occurred.

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

The posted primary outcome is a comparison of participant counts during a 100-day timeframe after HSCT. The registry records five TA-TMA events in the NAC group and fifteen in the placebo group, with group sizes of 66 and 77. The accompanying risk-difference estimate is -0.119, and the unadjusted p-value is 0.041. Taken together, these figures describe a lower observed event proportion in the NAC group in this registry comparison, with uncertainty around the estimated difference.

That description does not establish that NAC works, does not work, or is appropriate for any individual. A statistical comparison is not medical advice and does not determine treatment decisions. The registry result alone also cannot establish how the result would apply to patients outside the enrolled trial population, or to settings with different transplant practices, diagnostic criteria, or follow-up. Detailed eligibility and treatment-regimen information are not reported in the registry record.

The confidence interval for the risk difference lies on the negative side of zero but approaches zero at its upper end. This supports describing the observed contrast as favoring a lower event proportion in the NAC group, while recognizing uncertainty in its size. The p-value is unadjusted, and the record does not report a multiplicity procedure or a detailed statistical plan. The registry also does not provide numeric results for the named secondary outcomes.

Important information for judging robustness is absent: the randomization procedure, masking details, analysis populations, missing-data methods, and explanation of the endpoint group sizes relative to the listed enrollment. Safety counts are available, but their time window and event definitions are not. These limitations mean the results should be understood as the posted registry comparison, rather than a complete account of trial conduct or a definitive evaluation of all benefits and risks.

16. Why This Trial Matters Statistically

This study illustrates why an event count should be read together with group sizes, an effect estimate, and its uncertainty. The raw primary counts are five events in the NAC group and fifteen in the placebo group. The risk difference of -0.119 expresses the direction and scale of the observed contrast, while its confidence interval conveys uncertainty. Neither the counts nor the unadjusted p-value alone describes the full strength or practical importance of the evidence.

The randomized, double-masked design is relevant because those methods can help limit systematic differences and influence on outcome assessment. Yet design labels do not replace reporting of how randomization and masking were carried out or how participants were analyzed. The registry does not report those details. This demonstrates a broader statistical point: interpretation depends not only on a result, but also on the design, analysis population, outcome definition, and transparency of the analysis plan.

The trial also has multiple named outcomes. Without reported secondary results or a multiplicity approach, it is not possible to assess the pattern of evidence across outcomes or determine how secondary findings were handled. Likewise, the absence of a stated missing-data approach and analysis population restricts assessment of how the posted endpoint group sizes arose.

Finally, the sample-size illustrations show how planning depends on the target effect: planning for smaller effects requires more participants per arm under the stated assumptions. Those illustrations are not the trial’s original design rationale and are not a measure of observed power. Distinguishing planning calculations from trial results is essential to avoid overstating what a registry record can establish.

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 reporting gaps limit interpretation. The registry does not give detailed eligibility criteria, participant characteristics, the NAC dose or schedule, or the diagnostic and adjudication rules for TA-TMA. Although the primary endpoint timeframe is 100 days, details of how and when the endpoint was assessed are not reported. These omissions make it difficult to judge how consistently the outcome was measured or how closely the enrolled population matches other transplant populations.

The listed enrollment is 170, while the primary outcome groups have sizes of 66 and 77. The record does not explain this relationship or define the analysis population. Safety counts use different group denominators from the primary endpoint, and the reason is not reported. The registry does not describe withdrawals, exclusions, missing outcomes, adherence, or crossover. It is therefore not possible to determine from this record whether the comparison includes all randomized participants or how incomplete information was handled.

Although the study is labeled randomized and double-masked, the randomization method, allocation concealment, masked roles, and maintenance of masking are not described. The registry lists no analysis records and does not report a detailed statistical plan, interim analyses, adjustment for covariates, or multiplicity procedures. The named secondary outcomes have no numerical results in the registry entries. The safety report lacks event definitions, a stated observation period, and serious adverse-event terms. These limitations do not show that particular methods were absent; they identify details that are not reported in the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Safety and Efficacy Study of NAC in Patients With TA-TMA — NCT03252925.
• Registry record last updated 2022-02-14; status last verified 2021-12.
• Results first posted 2022-02-14.
• 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 describes NCT03252925, “A Safety and Efficacy Study of NAC in Patients With TA-TMA,” as a completed Phase 3 randomized, double-masked, parallel study sponsored by The First Affiliated Hospital of Soochow University. The listed enrollment is 170. The intervention was N-acetylcysteine, compared with a placebo oral tablet.

The primary outcome was TA-TMA incidence after HSCT over a 100-day timeframe. The posted counts were five events among 66 participants in the NAC group and fifteen among 77 in the placebo group. The comparison reports a risk difference of -0.119 and an unadjusted p-value of 0.041. Four secondary outcomes are named, but their numerical results are not included in the record details used for this account.

The registry does not report the detailed statistical plan, analysis populations, missing-data methods, multiplicity approach, or explanation of the group-size differences. The safety record lists serious adverse event, other adverse event, and death counts, but does not provide the event definitions or observation period needed for a full comparative safety interpretation.