Neurocircuit Strategy to Decrease Cocaine Cue Reactivity: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Neurocircuit Strategy to Decrease Cocaine Cue Reactivity (NCT04155632), a randomized phase 2 study. The primary outcome is Change in Orbitofrontal Cortex (OFC) BOLD Signal During Cocaine Cue Reactivity Task (Pre- vs. Post-TBS).

2. Clinical Question

3. Trial Design

This is a Phase 2, randomized, triple-masked, parallel-group study listed as completed in the registry. The Medical University of South Carolina is the sponsor. The registry reports enrollment of 32 participants. The study began on 2020-12-18, and its primary completion date is 2023-03-09.

The registry lists N-acetylcysteine as a drug intervention and theta-burst stimulation as a device intervention. Four treatment combinations are named: N-acetylcysteine with active TBS, N-acetylcysteine with sham TBS, placebo with active TBS, and placebo with sham TBS. The arm descriptions do not provide additional treatment details. The posted primary outcome results, however, are reported by active versus sham TBS, with 16 participants in each stimulation group. They do not provide a separate comparison by drug assignment or by each of the four combinations.

The registry describes the overarching goal as examining the effect of combining TBS and NAC on cocaine craving and brain response to cocaine-related images. The posted primary endpoint addresses the brain-response component: change in OFC BOLD signal during a cocaine-cue reactivity task. The timeframe is from baseline to immediately post-TBS. The registry lists three outcome measures, but secondary outcome results are not posted. Randomization and masking are recorded, but details of the randomization procedure, masking roles, treatment schedule, and analysis 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: Only 32 were randomized and started treatment.

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 Change in Orbitofrontal Cortex (OFC) BOLD Signal During Cocaine Cue Reactivity Task (Pre- vs. Post-TBS), measured over From baseline to immediately post-TBS.

The primary endpoint is the change in orbitofrontal cortex (OFC) BOLD signal during a cocaine-cue reactivity task, measured from baseline to immediately after TBS. Functional MRI was used to measure the signal during blocks of cocaine-related images compared with neutral-image blocks. In broad terms, BOLD signal is an imaging measure of changes in brain response; it is not a direct measure of craving, behavior, or treatment benefit.

The registry describes the outcome as a change between baseline (Visit 2) and post-TBS (Visit 3). Although one part of the description uses the phrase percent BOLD signal change, it also explicitly states that the reported values are raw BOLD signal units, not percentages. The reported group summaries and comparison should therefore be interpreted in those raw units.

An imaging endpoint can quantify a targeted brain response under a defined task condition. Here, the contrast between cocaine-related and neutral image blocks is intended to capture cue-related brain activation. The result answers a narrow measurement question about change in OFC signal over the stated interval. It does not, by itself, establish whether craving changed or whether any broader clinical outcome changed; those results are not reported in the registry record.

7. Results Posted in the Registry

• Active Theta Burst Stimulation: mean -0.00 versus 0.00 on control; difference -0.00 (95% CI -0.01 to 0.00), standardized effect d = -0.35; z-test p = 0.317.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted endpoint is continuous, and the registry identifies the reported group value as a mean with standard deviation. A mean describes the central value of a set of measurements. A standard deviation describes how spread out individual measurements are around that mean. In general, these are different summaries: the standard deviation reflects participant-to-participant variability, whereas a confidence interval around a mean or contrast reflects uncertainty in estimating a population quantity.

What does the mean difference represent?

The reported contrast is the mean change in the active TBS group minus the mean change in the sham TBS group. The group means are -0.003 and 0.001, respectively, and the reported mean difference is -0.003. A negative contrast means that the active-group mean is lower than the sham-group mean on the stated change scale. This is a comparison of group averages; it does not mean that every participant changed in the same direction.

In general, a mean difference retains the endpoint's measurement units, so its interpretation depends on how the outcome was defined. In this study the registry says the values are raw BOLD signal units, not percentages. The result is consequently best understood as a difference in the recorded raw signal-change scale, rather than a relative percentage change.

What does the confidence interval add?

A confidence interval gives a range of estimates compatible with the observed data under the method used to calculate it. The reported 95% confidence interval for the mean difference is -0.010 to 0.003. It expresses uncertainty about the group contrast, not the range containing 95% of individual participants' measurements. Because the interval includes zero, it includes no difference as one value compatible with the data, while also including negative and positive contrasts. The registry does not report enough detail to identify all assumptions or the precise calculation method behind the interval.

How should the p-value be read?

The unadjusted p-value is 0.317. In general, a p-value measures the compatibility of the observed data with a specified null model, assuming that model and its assumptions. It is not a measure of the size or importance of the effect, and it is not the probability that the null model is true. The record does not report an adjusted p-value or a detailed testing plan. The reported value should be read as an unadjusted result for this comparison, without assuming that it accounts for other outcomes or possible comparisons.

What does variation tell us?

The standard deviation is 0.008 in the active group and 0.011 in the sham group. In general, more variability makes group means harder to estimate precisely when the amount of data is otherwise similar. The standard deviations describe variability in observed change scores, while the confidence interval describes uncertainty in the estimated difference. They are related to precision but are not interchangeable. The registry does not report individual-level data, so the spread, distribution shape, and possible outliers cannot be assessed from the summary values alone.

What can be learned from planning illustrations?

Planning figures use the observed contrast as a reference and show hypothetical participant requirements for detecting stated fractions of that contrast. They are not a retrospective assessment of the study's ability to find an effect. The calculations use a two-sided significance level of 0.05, equal allocation, and a normal approximation; the original trial's design assumptions are not reported in the registry record. General sample-size calculations depend on the effect size to be detected, the variability of the outcome, the significance level, and the desired power. Smaller target effects generally require more participants, all else being equal. Those planning calculations do not change the interpretation of the observed mean difference or its interval.

In general, over-dispersion means that observed variability exceeds what a chosen statistical model assumes. If present, it can make standard errors and confidence intervals from that model too optimistic unless the analysis accounts for it. The registry does not report a model-based analysis or a check for over-dispersion, and the posted summaries do not establish whether it is relevant for this continuous endpoint. The comparison is therefore best described using the statistics actually posted, without attributing a particular model or diagnostic procedure to the investigators.

The registry identifies the comparison as a mean difference and provides group means, standard deviations, confidence limits, and an unadjusted p-value. It does not report the analysis population, handling of missing measurements, covariate adjustment, or model specification in the registry record. No further analytic details should be inferred from the summary statistics alone.

10. Confidence Intervals and Precision

The estimated mean difference in change between active and sham TBS was -0.003 raw BOLD signal units. Its 95% confidence interval runs from -0.010 to 0.003. The interval includes zero and extends into both negative and positive values, so the data do not pinpoint the direction of the underlying group difference with high precision. The interval is the main guide to the range of contrasts compatible with the reported analysis.

A confidence interval is not a statement that most participants had changes inside its limits. It concerns uncertainty about the group-level contrast. Individual variation is described separately by the standard deviations: 0.008 for active TBS and 0.011 for sham TBS. The observed result combines a point estimate with uncertainty; the point estimate alone does not show how precisely the contrast is estimated.

The interval's width matters because multiple values remain compatible with the observed data. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. The registry record does not give a clinically meaningful threshold for this signal measure, so the interval cannot be classified against a reported threshold for practical importance. Nor does the record report a minimum important difference for the endpoint.

The unadjusted p-value is 0.317. It should not replace the interval as a description of precision: the interval shows the range and direction of plausible contrasts, while the p-value summarizes compatibility with a null model under the test's assumptions. Full details of the interval and test procedures are not reported in the registry record.

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 figures are participants per arm, not total events. They illustrate hypothetical requirements for 80% or 90% power under the stated assumptions; the registry record does not report the assumptions used to design the original trial. The calculations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect.

For planning based on 100% of the observed effect, the illustration gives 126 participants per arm for 80% power and 169 participants per arm for 90% power. For 75% of the observed effect, it gives 224 participants per arm for 80% power and 299 participants per arm for 90% power. For 50% of the observed effect, it gives 503 participants per arm for 80% power and 673 participants per arm for 90% power.

In plain terms, the 80% power column gives a hypothetical number per arm for a design with an 80% chance of detecting the selected effect under the calculation assumptions, if that effect and assumptions were true. The 90% power column describes the corresponding planning target for a higher chance of detecting that effect. Smaller effects require more participants, all else being equal, which is why the illustrative participant requirements rise as the fraction of the observed effect becomes smaller.

These figures are planning illustrations based on the observed result, not observed power and not evidence about the probability that the trial's result is correct. They also do not establish what enrollment the investigators originally planned or whether any original design target was met.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.003; pooled standard deviation σ = 0.009.
2. n = 2 × (1.96 + 0.842)² × 0.009² / -0.003² = 125.6, rounded up to 126 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 <- -0.0033                      # observed difference in means
sigma <- 0.00933407735129723                     # 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(4155632)
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 = 126 (80% power), 169 (90% power)
 75% of observed effect: n per arm = 224 (80% power), 299 (90% power)
 50% of observed effect: n per arm = 503 (80% power), 673 (90% power)
power.t.test: 126.6 
Simulated power at n = 126 per arm: 0.797 (20000 replicates)

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

13. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures, but no secondary outcome results are posted. The primary result includes an unadjusted p-value of 0.317. No adjusted p-value or multiplicity procedure is reported in the registry record. Multiplicity concerns the risk of misleading results when several outcomes, comparisons, or analyses are tested; in general, an analysis plan may specify how such testing is handled. The record does not state whether or how that issue was addressed.

The study names four combinations of NAC or placebo with active or sham TBS, while the posted primary comparison groups participants by active versus sham TBS. Separate primary-result estimates for the drug assignment, each combination, or an interaction between interventions are not reported in the registry record. It is therefore not possible to determine from these posted results how comparisons across the four named combinations were planned or analyzed.

Missing-data handling is not reported in the registry record. The posted arm summaries include 16 participants in each stimulation group, but the record does not state whether every enrolled participant contributed a baseline and post-TBS measurement, how incomplete imaging data were handled, or which analysis population was used. The total enrollment should not be assumed to be identical to the number analyzed for every outcome without that information.

The registry does not report a protocol-specific statistical analysis plan, covariate adjustment, interim analyses, or the intended analysis population. Those details are important for understanding whether the displayed comparison was prespecified and how decisions about exclusions or incomplete outcomes were made. Their absence limits assessment of the analysis process but does not alter the numerical result that is posted.

14. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry reports serious adverse event counts for the active and sham TBS groups. In each group, 16 participants were listed as at risk and zero serious adverse events were reported. The record also lists zero other adverse events and zero deaths in each group. No serious-event terms are listed.

These are counts recorded in the registry, not a detailed safety analysis. The record does not provide event definitions, timing, severity grading, attribution, or information about how adverse events were collected. It also does not report a separate safety summary by NAC versus placebo assignment or by each of the four named treatment combinations. The counts should therefore be read as the posted group-level figures, without inferring details that are not reported.

A count of zero in a group does not establish that a treatment is free of risk, especially when the registry record contains limited information about event ascertainment and follow-up. These figures describe what was reported for this study and do not support conclusions about safety in other settings or populations.

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

The posted result describes change in an imaging measure during a cocaine-cue task. The estimated mean change was -0.003 in the active TBS group and 0.001 in the sham TBS group; the active-minus-sham mean difference was -0.003 raw BOLD signal units. Its 95% confidence interval, -0.010 to 0.003, includes zero. The result is compatible with a range of group differences, including contrasts in either direction, and is not a precise estimate of a single underlying value.

This endpoint concerns OFC signal during a task contrasting cocaine-related and neutral images. It does not directly measure craving, substance use, functioning, or another clinical outcome. Although the study's stated goal includes craving and brain response, the registry does not post a craving result among the results. The record therefore does not establish what happened to craving.

The comparison is active versus sham TBS in the posted results. The study also lists NAC and placebo combinations, but does not provide separate outcome estimates for those assignments. The result cannot isolate the contribution of NAC, determine an interaction between NAC and TBS, or rank the four listed combinations.

The confidence interval and unadjusted p-value should not be translated into a claim that active TBS did or did not work. They describe uncertainty and compatibility for this specific statistical comparison. The registry does not provide a clinically meaningful threshold for the BOLD signal change, and the posted result is not enough to establish the practical significance of the estimated difference. It is a limited, endpoint-specific finding from a completed Phase 2 study, rather than a general conclusion about treatment or clinical outcomes.

16. Why This Trial Matters Statistically

This study illustrates why the contrast, measurement scale, and uncertainty all matter when interpreting a clinical-trial result. The endpoint is change in OFC BOLD signal during a task, not a direct patient-reported or clinical outcome. The registry explicitly identifies the reported values as raw signal units, which helps prevent a mistaken reading of them as percentages.

The mean difference provides a direction and size for the observed group contrast, while the confidence interval communicates its uncertainty. Here the interval includes both negative and positive values and zero. Reporting both the estimate and its interval gives a more complete account than focusing on the point estimate or the unadjusted p-value alone.

The design also raises questions about how combined interventions are interpreted. NAC and TBS are both part of the study's stated goal, and four treatment combinations are listed, but the posted primary result is grouped only by active versus sham TBS. Without separate results by drug assignment, readers cannot distinguish a TBS contrast from a drug contrast or an interaction using the posted primary numbers.

Finally, the planning illustrations emphasize that sample-size requirements depend on the effect a study aims to detect. Smaller effects require more participants under the stated assumptions. Those calculations are useful for understanding hypothetical design requirements, but they do not reconstruct the investigators' original rationale, which is not reported in the registry record, and they do not alter the uncertainty in the observed result.

17. Limitations

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

The registry reports enrollment of 32 and group summaries for 16 participants in each stimulation group. The record does not provide participant characteristics, so it is not possible to assess how representative the enrolled group may be of people with cocaine-related disorders more broadly. Eligibility criteria and recruitment details are also not reported in the registry record.

The primary endpoint is an immediate post-TBS change in one specified imaging measure. The posted result does not describe persistence of the signal change at later time points. It also does not provide a posted craving result, although craving is part of the study's stated overarching goal. Findings for the imaging endpoint should not be extended to those unreported outcomes.

The registry lists four combinations of NAC or placebo and active or sham TBS, but the primary result is presented as an active-versus-sham stimulation comparison. There are no separate posted results by drug assignment or treatment combination, limiting interpretation of the contribution of NAC and any joint effect of the interventions.

Important analysis details are not reported in the registry record, including missing-data handling, the analysis population, covariate adjustment, and the statistical analysis plan. The outcome description includes both percent-change wording and an explicit statement that the reported values are raw BOLD signal units, not percentages; interpretation should follow that explicit clarification. The registry also does not state a clinically meaningful threshold for this measure. These limitations constrain interpretation of the magnitude and generalizability of the posted result.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Neurocircuit Strategy to Decrease Cocaine Cue Reactivity — NCT04155632.
• Registry record last updated 2025-09-24; status last verified 2025-09.
• Results first posted 2025-09-24.
• 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

NCT04155632 is a completed, randomized, triple-masked, parallel Phase 2 study sponsored by the Medical University of South Carolina. It enrolled 32 participants and examined theta-burst stimulation and N-acetylcysteine in cocaine-related disorders. The registry lists four combinations of NAC or placebo with active or sham TBS.

The primary endpoint is change in OFC BOLD signal during a cocaine-cue reactivity task from baseline to immediately post-TBS. The posted active-versus-sham mean difference was -0.003 raw BOLD signal units, with a 95% confidence interval from -0.010 to 0.003 and an unadjusted p-value of 0.317. The interval includes zero. Secondary outcome results and separate estimates by NAC assignment are not reported in the registry record.