Modafinil and Naltrexone to Reduce Cocaine and Alcohol Dependence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Modafinil and Naltrexone to Reduce Cocaine and Alcohol Dependence (NCT00142818), a randomized phase 2 study. The primary outcome is Cocaine Use (Measured by Timeline Follow Back and Urine Screen From Week 2-week 14).

2. Clinical Question

The central comparison is whether the posted group summaries differ in the number of negative urine samples. The registry record reports means and standard deviations by group, along with unadjusted mean differences and confidence intervals for comparisons against naltrexone with placebo. Those statistics describe the observed data and the precision of the estimated contrasts. They do not by themselves establish that a group difference was caused by the assigned medication, nor do they answer every question about use, safety, or longer-term outcomes.

3. Trial Design

The registry describes a completed, randomized, quadruple-masked, parallel-group Phase II pilot trial. Its official title identifies it as double-blind and placebo-controlled, while the design fields report quadruple masking. The registry record does not specify which people or roles were included in the masking description, so the exact masking arrangements cannot be reconstructed from the posted details.

The study enrolled 164 participants. Four groups are reported: naltrexone plus modafinil, with 45 participants; naltrexone and placebo, with 40; modafinil and placebo, with 37; and double placebo, with 42. These are the group sizes reported for the primary outcome. The registry record does not describe the allocation ratio, the randomization sequence, or how allocation was concealed.

The listed primary-outcome comparisons use naltrexone and placebo as the reference group. The other comparisons are the combination group, modafinil and placebo, and double placebo. Although the trial includes four groups and two active medications, the registry record does not report enough detail to characterize the design as a particular factorial or other specialized design.

The study began in 2006-02, had primary completion in 2013-08, and is marked completed. The endpoint timeframe is 13 weeks. The record identifies the trial as a pilot, but it does not report the original sample-size justification or the design assumptions used when the study was planned. It also does not report whether interim analyses were planned or conducted. Those details should not be inferred from the planning illustrations calculated from the observed results.

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 Cocaine Use (Measured by Timeline Follow Back and Urine Screen From Week 2-week 14), measured over 13 weeks.

The primary outcome is the mean number of cocaine-negative urine samples, measured by Timeline Follow Back and urine screening from week 2 to week 14. The registry lists the timeframe as 13 weeks and identifies the outcome as a mean of a continuous measure, with standard deviation as its dispersion statistic. Each participant’s outcome is expressed as a number of negative urine samples; the reported group mean summarizes those participant-level values.

Urine screening provides an observed test result at the occasions when samples are collected. Timeline Follow Back is also named as part of the measurement approach. The registry record does not describe how the two sources were combined, how often samples were scheduled, how missing or unusable samples were handled, or whether self-report contributed to the numerical endpoint. Those measurement details are not reported in the registry record.

This outcome is used to quantify cocaine-negative samples during the stated follow-up period, allowing group averages to be compared. A group mean is a summary rather than a description of every participant’s pattern. It does not show the distribution of individual outcomes, the timing of any use, or alcohol use. The primary endpoint is specifically about cocaine-negative urine samples, so it should not be treated as a complete measure of either dependence or all substance-use outcomes.

7. Results Posted in the Registry

• ModNal: mean 9.30 versus 7.20 on control; difference 2.10 (95% CI -1.41 to 5.61), standardized effect d = 0.25; z-test p = 0.241.
• Modafinil and Placebo: mean 10.10 versus 7.20 on control; difference 2.90 (95% CI -1.03 to 6.83), standardized effect d = 0.33; z-test p = 0.148.
• Double Placebo: mean 10.50 versus 7.20 on control; difference 3.30 (95% CI -0.61 to 7.21), standardized effect d = 0.36; z-test p = 0.098.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a quantitative measure summarized by a mean and standard deviation. A mean is the arithmetic average of participant-level values. Here the values are numbers of cocaine-negative urine samples. A standard deviation describes how dispersed participant values are around their group mean; it is not the same as the uncertainty in the mean or the range containing most participants. The reported standard deviations are 8.4 in the combination group, 8.1 in the naltrexone-and-placebo group, 9.4 in the modafinil-and-placebo group, and 9.9 in the double-placebo group.

The mean difference compares a group mean with the reference group mean. For example, the reported contrast for the combination group is 2.1, comparing its mean of 9.3 with the reference mean of 7.2. The other contrasts are 2.9 for modafinil and placebo and 3.3 for double placebo, each against the same reference. These estimates are unadjusted and are expressed on the original outcome scale, as numbers of negative urine samples. A positive difference means the comparison group’s reported mean is higher; it does not by itself explain why the means differ.

A confidence interval describes a range of estimates compatible with the observed data under the calculation’s assumptions. In general, a 95% confidence procedure is constructed so that, over repeated samples under its assumptions, intervals would cover the target quantity at the stated rate. It does not mean that there is a 95% probability that this particular fixed interval contains the true value. The intervals reported for the three contrasts each extend across zero, indicating that the posted estimates do not sharply distinguish positive from negative differences.

The p-values are unadjusted. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that null hypothesis and the statistical assumptions held. It is not an effect-size measure, does not describe the probability that the null is true, and does not tell whether an observed difference is important. The posted values are 0.241 for the combination comparison, 0.148 for modafinil and placebo, and 0.098 for double placebo. The registry record does not report whether the investigators used a different inferential procedure or how they handled multiple comparisons.

The standard deviations differ across the groups, and the endpoint is a count of negative samples. In general, when outcome variability is greater than a model assumes, standard errors and confidence intervals based on that model can be too narrow, and test results can be misleading. This is the general concern often described as over-dispersion. The registry record does not describe a distributional model, a check for over-dispersion, or a method for addressing it. No such analysis should be presumed from the means and standard deviations alone.

The recalculated contrasts use the posted group means, standard deviations, and group sizes and are labeled unadjusted. They do not account for baseline measures, other participant characteristics, repeated observations, or missing outcome values. The registry record does not report whether such adjustments were used in the investigators’ own analysis. It also does not report a detailed analysis plan, model specification, handling of protocol deviations, or the population included in the primary analysis. These omissions limit the extent to which the reported summaries can be treated as a full account of the statistical analysis.

The planning illustrations use a normal approximation, a two-sided significance level of 0.05, and equal allocation between the two arms. They are based on the observed effect, with planning scenarios that target a stated fraction of that effect. In general, a normal approximation estimates the sample size using assumptions about the distribution of an estimate, and a two-sided test allows departures in either direction. These planning conditions describe the illustrations, not the trial’s original design. The original sample-size assumptions are not reported in the registry record.

Statistical methods are useful only to the extent that their assumptions and the underlying data are suitable. Group averages do not show how observations were distributed, whether measurements were missing, or whether participants contributed the expected outcome information. Without those details, the posted mean comparisons can be interpreted as summaries of the available record, but the analytic choices behind a full trial inference remain uncertain.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data estimate a group contrast. The recalculated unadjusted mean difference for naltrexone plus modafinil versus naltrexone and placebo is 2.1, with a 95% confidence interval from -1.411 to 5.611. The interval includes zero and extends to both negative and positive values, leaving uncertainty about the direction as well as the size of the contrast.

For modafinil and placebo versus naltrexone and placebo, the estimated difference is 2.9 and the 95% confidence interval runs from -1.034 to 6.834. For double placebo versus naltrexone and placebo, the estimated difference is 3.3 and the interval runs from -0.607 to 7.207. These intervals also include zero and allow a range of possible contrasts in either direction. The reported p-values are unadjusted: 0.148 for modafinil and placebo and 0.098 for double placebo, alongside 0.241 for the combination group.

In general, a wider confidence interval reflects greater uncertainty about the estimate, while a narrower interval indicates more precision under the method’s assumptions. Interval width depends on factors including sample size and outcome variability. The primary-outcome group sizes range from 37 to 45, and the reported standard deviations range from 8.1 to 9.9. The registry does not report a precision target for the original study design.

The intervals are recalculated from posted summary statistics and should not be confused with an adjusted model’s intervals. They quantify uncertainty in these unadjusted contrasts under the calculation used, not uncertainty about every aspect of study conduct, measurement, or generalizability. Their breadth means the results do not tightly locate the group differences.

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 apply to the two-arm comparisons and use equal allocation between the two arms. The stated planning assumptions are a two-sided significance level of 0.05 and a normal approximation. The assumed effect is set to the stated fraction of the observed effect. These are planning illustrations computed from the observed result; the trial’s original design assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm estimated to yield an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the assumptions were correct. The 90% power column gives the corresponding estimate for a 90% chance. Power is a design property under an assumed effect and statistical model, not a guarantee that a result will be detected or that an observed result is true.

The rows for 100%, 75%, and 50% of the observed effect describe different assumed effects. When the target effect is smaller, it is harder to distinguish from random variation, so more participants are needed for the same planned power. The estimates vary by comparison because each observed contrast has a different magnitude and variability. They should not be interpreted as the sample size used in this completed trial or as evidence about what its design team originally planned.

This is not observed power. It is a prospective-style planning calculation using an effect estimated from the observed data, and its results depend on the stated assumptions. Since the observed effect itself is uncertain, the planning figures are illustrative rather than a definitive prescription for a future study.

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 = 2.100; pooled standard deviation σ = 8.260.
2. n = 2 × (1.96 + 0.842)² × 8.260² / 2.100² = 242.9, rounded up to 243 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 <- 2.1                      # observed difference in means
sigma <- 8.26039323431652                     # 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(142818)
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 = 243 (80% power), 326 (90% power)
 75% of observed effect: n per arm = 432 (80% power), 579 (90% power)
 50% of observed effect: n per arm = 972 (80% power), 1,301 (90% power)
power.t.test: 243.8 
Simulated power at n = 243 per arm: 0.801 (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 two outcome measures and one analysis, and no secondary outcome results are posted. For the primary outcome, three contrasts are reported against the same naltrexone-and-placebo reference group. The p-values are labeled unadjusted. Testing several contrasts can raise a multiplicity question because the chance of at least one apparently unusual result can change when multiple hypotheses are considered. The registry record does not report a family of primary comparisons, a multiplicity adjustment, or a prespecified hierarchy for interpreting the contrasts.

The record also does not report a detailed statistical analysis plan, the timing of any analysis decisions, interim analyses, or whether the reported contrasts were prespecified. This absence does not establish that no such plans or procedures existed; it means they are not reported in the registry record. The status of the primary outcome as the main endpoint is clear, but the inferential role of each comparison is not described in detail.

Missing-data handling is also not reported in the registry record. The posted primary-outcome sample sizes are 45, 40, 37, and 42 across the four groups, but the record does not explain whether these are all randomized participants, participants with observed outcomes, or a particular analysis population. It does not state how unavailable urine samples, incomplete follow-up, or other missing values were treated. The registry record therefore does not support assumptions such as complete-case analysis, imputation, or an intention-to-treat analysis.

The analysis population is not reported in the registry record. Details about adherence, exclusions after randomization, protocol deviations, and participant flow are likewise not reported. These details matter because the interpretation of a randomized comparison depends partly on which participants and outcome observations were included. Without them, the group summaries and recalculated contrasts remain useful descriptions of posted results, but they do not reveal all choices that may have affected the analysis.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hospitalization (16.7%), exacerbation of cocaine and alcohol (14.3%), arrested for homicide (2.5%), depression or hallucinations (2.4%).

The serious-adverse-event figures report 11 participants affected in the naltrexone-plus-modafinil group, among 45 at risk; 6 in the naltrexone-and-placebo group, among 40 at risk; 6 in the modafinil-and-placebo group, among 37 at risk; and 11 in the double-placebo group, among 42 at risk. These are counts, not comparisons adjusted for differences in follow-up or other factors. The registry record does not provide deaths counts; the death entries are not reported in the registry record.

The other-adverse-event counts are 11 among 45, 10 among 40, 8 among 37, and 4 among 42, respectively, in the same group order. The record also lists serious-event terms with accompanying percentages: Hospitalization, 16.7%; Exacerbation of cocaine and alcohol, 14.3%; Arrested for Homicide, 2.5%; and Depression or Hallucinations, 2.4%. The registry entries do not establish from these figures alone how the term percentages relate to individual participants or groups, so they should not be read as group-specific risks.

Counts of affected participants do not show event severity, duration, recurrence, or causal attribution. They also do not establish a comparative safety profile. Definitions, event narratives, and detailed methods for collecting and classifying adverse events are not reported in the registry record. These figures describe what was posted and should be interpreted with those limitations.

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

The posted primary-outcome summaries show different mean numbers of cocaine-negative urine samples across the four randomized groups. The reported means are 9.3 for the combination, 7.2 for naltrexone and placebo, 10.1 for modafinil and placebo, and 10.5 for double placebo. The unadjusted recalculated contrasts against naltrexone and placebo are positive for all three comparison groups, but every confidence interval extends across zero. The estimates therefore do not precisely establish the direction or size of the differences.

These statistics are about a specific endpoint during a stated follow-up period. They do not report alcohol-use outcomes, later follow-up, or every dimension of cocaine dependence. A mean does not indicate how many individuals had a particular outcome, how outcomes changed over time, or whether some participants had very different patterns from the group average. The registry record does not include participant-level data that would resolve those questions.

The reported comparisons are unadjusted recalculations from group summaries. The registry record does not report the analysis population, missing-data approach, or adjusted model results. It also does not report enough detail to establish the original analysis plan or how multiple comparisons were handled. Such uncertainties are relevant when interpreting the apparent size and precision of group contrasts.

The statistics do not establish that a medication caused a difference, that one group’s result applies to other populations, or that any treatment should be used. They characterize the posted trial results and their uncertainty, not an individual participant’s likely outcome or a clinical decision. The trial’s pilot designation and the reported group sizes also mean the findings should be read as a limited study record rather than a complete answer to every question about the medication combination.

16. Why This Trial Matters Statistically

This trial is statistically instructive because it reports four groups and several contrasts on a single continuous primary outcome. The mean difference is expressed on the original outcome scale, making its direction understandable as a difference in the number of cocaine-negative urine samples. At the same time, the standard deviations are large relative to the group means, and the confidence intervals are broad enough to include zero and values on either side. This illustrates why an estimated contrast should be read together with its uncertainty.

The study also highlights the distinction between posted group summaries and a complete inferential analysis. Means, standard deviations, group sizes, and unadjusted contrasts make several features of the results visible. They do not tell readers how missing samples were handled, what analysis population was used, whether covariates were included in an investigator analysis, or how multiple comparisons were addressed. Those decisions affect how an analysis should be interpreted, but they are not reported in the registry record.

The sample-size illustrations show a further statistical point: planning depends on the effect one aims to detect. Smaller assumed effects require more participants to reach a given planned power when other assumptions are held fixed. Since these illustrations use the observed effects rather than the original design assumptions, they should not be confused with the trial’s actual planning process or used as evidence of observed power.

Finally, safety counts and efficacy-related outcomes answer different questions. Serious-event counts describe affected participants as posted, while the primary outcome summarizes negative urine samples. Neither type of statistic alone provides a complete account of clinical outcomes. Reading the results with attention to endpoint, precision, analysis details, and missing information helps keep statistical conclusions proportionate to what the registry record reports.

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 primary endpoint is narrowly defined as the number of cocaine-negative urine samples over the reported 13-week timeframe. Although Timeline Follow Back and urine screening are named, the registry record does not describe the exact measurement schedule, how self-report and screening were combined, or how missing or unusable samples were handled. This makes it difficult to assess the endpoint’s operational details from the record alone.

Outcome summaries are posted for groups of 45, 40, 37, and 42 participants. The record does not explain whether these counts represent randomized participants or participants with usable primary-outcome data, and the analysis population is not reported. Participant flow, adherence, protocol deviations, and exclusions are also not described. The reported group results therefore cannot be assumed to include every randomized participant under a particular analysis principle.

The available comparisons are unadjusted recalculations from group summary statistics. The registry record does not report a sponsor analysis result, an adjusted model, covariate choices, or the method used in the investigators’ analysis. The record also does not explain whether or how multiplicity was addressed across the three contrasts. These gaps limit interpretation of the inferential status of the reported p-values and confidence intervals.

The trial is identified as a Phase II pilot, but the original sample-size justification and design assumptions are not reported. Interim analyses and detailed eligibility criteria are not reported either. The long interval between the recorded start and primary completion does not by itself explain recruitment, follow-up, or operational history. Finally, the safety information includes counts and selected serious-event terms, but detailed event-level information and death counts are not reported in the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Modafinil and Naltrexone to Reduce Cocaine and Alcohol Dependence — NCT00142818.
• Registry record last updated 2020-07-16; status last verified 2020-07.
• Results first posted 2014-08-29.
• 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

NCT00142818 is a completed randomized, quadruple-masked, parallel-group Phase II pilot trial of modafinil and naltrexone for cocaine and alcohol dependence. The study enrolled 164 participants into four reported groups: naltrexone plus modafinil, naltrexone and placebo, modafinil and placebo, and double placebo.

The primary outcome was the mean number of cocaine-negative urine samples measured using Timeline Follow Back and urine screening from week 2 to week 14, over a 13-week timeframe. The posted group means range from 7.2 to 10.5. Recalculated unadjusted comparisons against naltrexone and placebo have confidence intervals that include zero.

The registry record does not report the original sample-size assumptions, missing-data handling, analysis population, or detailed statistical plan. Planning figures based on observed effects are illustrations rather than the trial’s original design assumptions.