Effectiveness of N-Acetylcysteine (NAC) in Treating Cocaine Dependent Individuals - 1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effectiveness of N-Acetylcysteine (NAC) in Treating Cocaine Dependent Individuals - 1 (NCT00218491), a randomized phase 2 study. The primary outcome is Number of Participants That Achieved Study Compliance.

2. Clinical Question

3. Trial Design

The registry describes a randomized, double-masked, parallel Phase 2 trial sponsored by the Medical University of South Carolina. Its recorded status is completed. The study start is listed as 2005-11 and primary completion as 2010-05. Enrollment is recorded as 111 participants. The three groups were 1200mg N-Acetylcysteine, 2400mg N-Acetylcysteine, and Matching Placebo, with reported group sizes of 40, 33, and 38 participants, respectively.

A parallel design assigns participants to a group and compares their outcomes across groups. Random allocation is intended to make group assignment independent of measured and unmeasured participant characteristics, although the registry record does not describe the allocation process or whether allocation concealment was used. Double masking means that the record characterizes the study as masked for more than one party, but it does not identify which people were masked or describe how masking was maintained. Those implementation details are not reported in the registry record.

The primary outcome was a count of participants meeting the study's compliance definition during 8 weeks. The registry lists one outcome measure and no posted secondary outcomes. It contains no posted statistical analyses for the outcome. The protocol's planned analysis, any prespecified group comparisons, analysis population, sample-size justification, and the original assumptions used to design the trial are not reported in the registry record. The sample-size illustrations associated with the posted effect estimates are planning calculations, not evidence of the original design rationale.

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

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 Number of Participants That Achieved Study Compliance, measured over 8 weeks.

The primary endpoint counts participants who achieved study compliance during 8 weeks. Compliance was defined as 80% or greater weekly urine riboflavin levels equal to or greater than 1500 ng/ml. Drug and placebo compliance were measured by urine riboflavin levels, according to the registry description. The endpoint therefore turns a repeated biomarker-based adherence measure into a binary participant-level outcome: each participant either meets the stated compliance definition or does not.

An adherence endpoint can help describe whether participants followed the study regimen well enough for an intervention comparison to be interpretable. It can also indicate whether a study's treatment procedures were feasible to carry out. However, compliance is distinct from the health outcome the intervention is intended to affect. The posted primary measure does not count cocaine use, abstinence, changes in dependence, or clinical improvement. It should be interpreted as the registry-defined measure of study compliance, not as a direct measure of treatment benefit.

The registry reports the count meeting the definition in each group: 22 participants among 40 assigned to 1200mg N-Acetylcysteine, 15 among 33 assigned to 2400mg N-Acetylcysteine, and 18 among 38 assigned to Matching Placebo. The record does not explain how missing weekly urine measurements were handled when classifying participants, nor does it report whether the threshold or measurement procedure changed during the study.

7. Results Posted in the Registry

• 1200mg N-Acetylcysteine: 55.0% (22/40) versus 47.4% (18/38) on control; risk difference 7.6 percentage points (95% CI -14.5 to 29.8), risk ratio 1.16 (0.75–1.80); unadjusted two-proportion z-test p = 0.500.
• 2400mg N-Acetylcysteine: 45.5% (15/33) versus 47.4% (18/38) on control; risk difference -1.9 percentage points (95% CI -25.2 to 21.3), risk ratio 0.96 (0.58–1.59); unadjusted two-proportion z-test p = 0.872.

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is binary at the participant level: a person either met the compliance definition or did not. The registry presents counts rather than a continuous measurement. For each dose comparison, the effect is expressed as a risk difference, which compares the proportion meeting the endpoint in the dose group with the proportion in the Matching Placebo group. A positive risk difference indicates a higher observed proportion in the dose group; a negative value indicates a lower observed proportion. This measure is on the absolute probability scale and is not a relative change.

What does the confidence interval describe?

A confidence interval expresses uncertainty around an estimated effect under the statistical method used. For a risk difference, zero represents no difference in the underlying proportions. An interval that includes values on both sides of zero is compatible with a lower proportion, no difference, or a higher proportion in the dose group, within the range of estimates the interval allows. Both reported intervals cross zero. This is why the observed direction of either point estimate should not be treated as a definitive direction for the underlying effect.

The intervals are based on small group counts, which limits precision. Their width conveys uncertainty that a single point estimate cannot show. A confidence interval is not a guarantee that the true effect lies inside it, and it does not assign probabilities to individual possible effects. It is a range generated by a procedure with stated long-run coverage properties when its assumptions hold. The registry does not identify the procedure used for any sponsor analysis because no analysis is posted; the intervals described for the group comparisons are unadjusted recalculations from the posted summary counts.

How should the p-values be read?

The reported unadjusted p-values are 0.5 for 1200mg N-Acetylcysteine versus Matching Placebo and 0.872 for 2400mg N-Acetylcysteine versus Matching Placebo. A p-value summarizes how inconsistent the data are with a null model of no group difference, assuming that model and the calculation's assumptions. It is not a measure of effect size, clinical importance, or the probability that the null hypothesis is true. The p-values do not show that the groups are identical, and they do not replace the estimates and intervals when describing uncertainty.

“Unadjusted” means these recalculations do not account for other variables or a multiplicity procedure. They use the posted summary counts and compare each dose group with placebo. No adjusted analysis, covariate set, or alternative modeling strategy is reported in the registry record. The original statistical analysis plan is also not reported, so these calculations should not be confused with a documented analysis selected in advance by the investigators.

Why use a risk difference?

A risk difference describes the absolute separation between the observed proportions in two groups. It is straightforward to interpret in terms of the endpoint probability, but it can depend on the setting and baseline outcome frequency. Other measures, such as a risk ratio or odds ratio, express comparisons on relative scales and answer different questions. The registry record contains recalculated relative measures as well, but the interpretation centers on the posted risk-difference comparisons and their uncertainty. Relative measures should not be read as interchangeable with absolute differences.

The primary outcome is based on whether a threshold is met, rather than on the full pattern of weekly riboflavin measurements. Dichotomizing a measurement can make a result easy to communicate, but it discards information about how far participants' measurements were above or below the threshold and about variation over time. The registry does not report analyses of the underlying weekly measurements, so their distribution and any patterns over the 8 weeks cannot be assessed.

What do the planning calculations represent?

The sample-size illustrations use the observed effect as their starting point and examine planning under alternative fractions of that effect. They are not the trial's original design calculations. They use a two-sided significance level of 0.05, equal allocation between the two groups in a comparison, and a normal approximation. The stated effect to detect is the selected fraction of the observed effect. For these non-time-to-event outcomes, the planning amounts refer to participants per arm.

These calculations answer a hypothetical planning question: how many participants per group would be indicated under those assumptions to detect an effect of the specified size at the stated power? They do not show the probability that the completed trial detected an effect, and they are not evidence that the observed estimates are true. When the effect chosen for planning is smaller, more participants are required under the same assumptions. The original protocol's sample-size assumptions and justification are not reported in the registry record.

These statistical concepts are general. The registry does not report enough detail to determine whether the investigators used these methods for their original analysis, how they handled deviations from the compliance definition, or whether they conducted interim analyses. No interim analyses or stopping rules are reported in the registry record.

10. Confidence Intervals and Precision

The reported risk-difference confidence intervals are broad and include zero for both dose comparisons. For 1200mg N-Acetylcysteine versus Matching Placebo, the point estimate favors a higher observed compliance proportion in the dose group, but the interval includes values in the opposite direction as well as no difference. For 2400mg N-Acetylcysteine versus Matching Placebo, the point estimate favors a lower observed compliance proportion in the dose group, while its interval also includes values in the opposite direction and no difference. The estimates therefore have limited precision for distinguishing the underlying group proportions.

Precision is different from whether an estimate is statistically significant. A wide interval indicates that the data do not pin down the effect closely. It can include both a modest difference and a larger difference, as well as the null value. The observed counts—22 of 40, 15 of 33, and 18 of 38—come from relatively small groups, so the amount of information available for each comparison is limited. The registry does not report an analysis that incorporates participant-level covariates or repeated measurements to refine these estimates.

The confidence intervals describe uncertainty in the group comparisons under the recalculation method; they do not address potential bias from missing data, outcome classification, or trial conduct. The record does not report how incomplete urine measurements were treated, so the intervals alone cannot resolve that uncertainty. Nor do they provide precision for cocaine-use outcomes, since the posted primary measure is compliance rather than cocaine use.

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 planning estimates are participants per arm for each two-group comparison, not total enrollment across all three trial groups. They are calculated using the observed effect and also consider planning for 75% of the observed effect and 50% of the observed effect. They are illustrations for planning a future comparison, not the sample size used to justify this completed trial. The registry's original sample-size assumptions are not reported in the registry record.

The stated 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 80% power column indicates the number of participants per arm that the calculation estimates would be needed to have an 80% chance of detecting an effect of that size under those assumptions, if the assumed effect and model apply. The 90% power column gives the corresponding planning amount for a 90% chance under the same assumptions. These are design targets, not descriptions of the probability that the completed trial detected an effect.

Planning for a smaller effect requires more participants under otherwise unchanged assumptions. The figures are sensitive to the observed effect used as their starting point, so they should not be treated as stable estimates of a future study's needs without considering whether that effect is a suitable planning value. The registry provides no independent justification for the observed effect as a target for a future study. These values are 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 = 0.474; treatment proportion p₁ = 0.550; average p̄ = 0.512.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7069 = 1.3855.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.7048 = 0.5932.
4. n = (1.3855 + 0.5932)² / (0.0763)² = 672.3, rounded up to 673 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 <- 0.473684210526316                          # control proportion
p1 <- 0.55                          # 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(218491)
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 = 673 (80% power), 900 (90% power)
 75% of observed effect: n per arm = 1,197 (80% power), 1,602 (90% power)
 50% of observed effect: n per arm = 2,694 (80% power), 3,606 (90% power)
power.prop.test: 672.3 
Simulated power at n = 673 per arm: 0.805 (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 lists one outcome measure and no posted secondary outcomes. It also lists no posted analyses. The record does not report a multiplicity adjustment, a hierarchy of outcomes, or a plan for handling multiple comparisons. The posted results include comparisons of each N-acetylcysteine dose with Matching Placebo; the unadjusted recalculations do not account for the number of comparisons. Without a documented analysis plan, it is not possible to determine whether these comparisons were prespecified or whether other comparisons were conducted.

The outcome description identifies a compliance threshold based on weekly urine riboflavin levels, but the registry does not explain how missing weekly measurements were handled. It does not state how many participants had missing measurements, whether participants with incomplete measurement were excluded, or whether any imputation or other missing-data method was used. The posted counts therefore show the reported numbers meeting the definition, but the record does not establish how missingness affected classification or the analysis.

The registry does not identify the analysis population. It is not reported whether the primary outcome was analyzed according to randomized assignment, among participants who began treatment, among participants with outcome measurements, or under another definition. The reported arm sizes and outcome counts should not by themselves be taken as confirmation of an intention-to-treat analysis. The disposition of participants after randomization and any exclusions from analysis are not reported in the registry record.

Other details that affect interpretation are likewise absent: the original statistical analysis plan, prespecified covariates, handling of protocol deviations, and any interim analyses are not reported. These omissions do not change the posted counts, but they limit assessment of whether the analyses followed a prespecified plan and how robust the findings are to missing or incomplete outcome data.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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 registry lists serious adverse events for 40 participants at risk in the 1200mg N-Acetylcysteine group, 33 in the 2400mg N-Acetylcysteine group, and 38 in the Matching Placebo group. The count affected by a serious adverse event is recorded as 0 in each group. This describes the serious adverse event figures posted in the registry; it does not establish that all possible harms were ruled out or that the treatment groups had identical safety profiles.

The record lists other adverse events affecting 32 participants in the 1200mg group, 28 in the 2400mg group, and 28 in the placebo group. These are separate from the serious adverse event counts. The registry does not provide the event terms in the registry record, and no leading serious-event terms are listed. Death counts are not reported in the registry record. The adverse event figures should be read as registry reporting, not as a complete account of the nature, severity, timing, or causal attribution of events.

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

The posted primary outcome shows how many participants in each group met the registry's operational definition of study compliance during 8 weeks. The risk-difference point estimate is positive for 1200mg N-Acetylcysteine compared with Matching Placebo and negative for 2400mg N-Acetylcysteine compared with Matching Placebo. In both comparisons, the confidence interval includes differences in either direction, and the unadjusted p-values are 0.5 and 0.872, respectively. The data do not establish a clear difference in compliance between either dose group and placebo.

This finding is not evidence that the groups are equivalent, because the intervals do not exclude differences in either direction. It is also not an estimate of the effect on cocaine use, abstinence, dependence symptoms, or other clinical outcomes. The primary endpoint concerns a urine-riboflavin-based compliance definition, and the registry lists no secondary outcomes. Conclusions about unposted outcomes cannot be drawn from these counts.

The record's omissions further limit what can be inferred. It does not report the original statistical analysis plan, participant-level analysis population, handling of missing weekly measurements, or original sample-size assumptions. The group comparisons are unadjusted recalculations from summary counts rather than posted sponsor analyses. They can describe the observed data, but they do not resolve possible effects of missing information or establish how the outcome was analyzed in the original trial.

The trial's recorded status is completed, with enrollment of 111 participants. Its results are best understood as a description of the posted compliance outcome and its uncertainty in the three randomized groups. The estimates do not by themselves establish efficacy or lack of efficacy for cocaine dependence, and they should not be used as medical advice.

16. Why This Trial Matters Statistically

This trial illustrates why the endpoint definition matters as much as the choice of statistical measure. The primary outcome is not a direct clinical outcome; it is a binary compliance classification derived from weekly urine riboflavin levels. The resulting group comparison answers a focused question about meeting that study definition. It does not automatically answer a question about cocaine use or clinical benefit. Clear separation of an adherence measure from a disease outcome prevents an estimate from being interpreted more broadly than the outcome supports.

The posted counts also illustrate the difference between an estimated direction and a precise conclusion. The dose comparisons point in opposite directions relative to placebo, while both confidence intervals span differences on both sides of zero. Reporting the point estimate alone would hide that uncertainty. The p-values likewise cannot establish equivalence or settle whether a difference is important; they need to be read alongside the effect measure, interval, endpoint definition, and group sizes.

Finally, the distinction between observed results and planning calculations is important. Planning illustrations based on observed effects can show how requirements change under hypothetical assumptions, but they do not reveal the trial's original design rationale or its observed power. The registry does not report the original sample-size justification, statistical plan, or handling of missing data. Those gaps make transparency about the scope of the available evidence especially important.

17. Limitations

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

The registry provides limited information about participant characteristics, eligibility criteria, recruitment, and treatment delivery. It records randomization and double masking, but does not describe the method of allocation, who was masked, or how masking was maintained. These details are not reported in the registry record, limiting assessment of implementation and generalizability.

The posted primary endpoint is a compliance measure, not a direct cocaine-use outcome. The record gives no secondary outcomes and no posted analyses. It does not report the handling of missing weekly urine measurements, the analysis population, participant exclusions, or protocol deviations. As a result, the reported counts cannot establish how incomplete observations or departures from the study procedures affected the endpoint.

The risk-difference estimates are unadjusted recalculations from summary counts; no sponsor analysis is posted. The original statistical analysis plan, any prespecified covariates, multiplicity strategy, interim analyses, and original sample-size justification are not reported. The sample-size illustrations are based on the observed effect and specified planning assumptions, not the trial's own design. The record also does not provide enough detail about adverse events to assess event types, timing, or causal attribution. Together, these limitations mean the posted results support a narrow description of compliance counts and uncertainty, rather than broad conclusions about clinical outcomes or the trial's full safety profile.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Effectiveness of N-Acetylcysteine (NAC) in Treating Cocaine Dependent Individuals - 1 — NCT00218491.
• Registry record last updated 2019-01-15; status last verified 2018-12.
• Results first posted 2019-01-15.
• 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 a completed, randomized, double-masked, parallel Phase 2 trial sponsored by the Medical University of South Carolina. It enrolled 111 participants with cocaine dependence and compared 1200mg N-Acetylcysteine, 2400mg N-Acetylcysteine, and Matching Placebo.

The primary outcome was the number of participants meeting the study-compliance definition during 8 weeks, based on weekly urine riboflavin levels. The posted counts were 22 of 40, 15 of 33, and 18 of 38, respectively. Unadjusted comparisons with placebo have confidence intervals spanning differences in both directions. No secondary outcomes or sponsor analyses are posted. The registry does not report the original analysis plan, missing-data handling, analysis population, or original sample-size justification.