Effectiveness of Modafinil and D-amphetamine in Treating Cocaine Dependent Individuals: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effectiveness of Modafinil and D-amphetamine in Treating Cocaine Dependent Individuals (NCT00218062), a randomized phase 2 study. The primary outcome is Cocaine Use as Assessed by the Treatment Effectiveness Score (TES), Which is the Total Number of Cocaine-negative Urines During Treatment.

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, quadruple-masked, parallel-group trial. The registry record lists an enrollment of 73 and a completed status. The listed study start is 2006-03, and primary completion is 2012-01. The sponsor was The University of Texas Health Science Center, Houston. The registry title is “Effectiveness of Modafinil and D-amphetamine in Treating Cocaine Dependent Individuals”; the official title is “Pharmacotherapy Dosing Regimen (Cocaine Dependence Population).”

The study examined d-amphetamine and modafinil when given alone and in combination, in the context of therapy. The posted primary outcome results compare three active-treatment groups with placebo plus therapy: d-amphetamine 60mg, modafinil 400mg, and modafinil 200mg combined with d-amphetamine 30mg. The intervention list also includes d-amphetamine 30mg, d-amphetamine 60mg, modafinil 200mg, modafinil 400mg, therapy, and placebo. The registry descriptions refer to outpatient treatment over 16 weeks and daily capsules, but full details for every arm are not reported in the registry record.

For the primary outcome, the registry states that all participants who received the first dose of study medication were included in the analysis. The arm-level outcome counts are 16 for d-amphetamine 60mg plus therapy, 11 for modafinil 400mg plus therapy, 10 for the combined medication group plus therapy, and 12 for placebo plus therapy. These outcome counts should not be assumed to equal the full randomized enrollment or to describe all trial participants. The registry record does not report the randomization procedure, allocation concealment, masking procedures, or the original statistical design assumptions.

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

Analysis population for the primary outcome, as defined in the registry: All participants who received the first dose of study medication were included in this analysis.

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 as Assessed by the Treatment Effectiveness Score (TES), Which is the Total Number of Cocaine-negative Urines During Treatment, measured over 16 weeks.

The primary endpoint was cocaine use assessed by the Treatment Effectiveness Score, defined in the registry as the total number of cocaine-negative urine samples during treatment. The measurement period was 16 weeks. For this continuous outcome, the registry reports each group’s mean number of negative urine samples and standard deviation.

A urine-based count provides an objective record of samples that tested negative during the treatment period, and the total count condenses repeated observations into a single participant-level measure. The resulting group mean describes the average count, while the standard deviation describes how spread out individual scores were around that mean. Neither the mean nor the standard deviation shows the full distribution of individual results.

The endpoint is useful for comparing groups on the amount of negative urine evidence accumulated over treatment, but its interpretation depends on how urine samples were scheduled, collected, and handled when missing. Those procedures and the missing-sample rules are not reported in the registry record. The endpoint also does not, on its own, describe other aspects of treatment or participants’ experiences. The posted results should therefore be read as comparisons of this specific measure over the stated treatment period, rather than as a complete account of all outcomes.

7. Results Posted in the Registry

• D-Amphetamine 60mg + Therapy: mean 9.25 versus 4.91 on control; difference 4.34 (95% CI -3.52 to 12.20), standardized effect d = 0.38; z-test p = 0.279.
• Modafinil 400mg + Therapy: mean 6.09 versus 4.91 on control; difference 1.18 (95% CI -5.25 to 7.61), standardized effect d = 0.15; z-test p = 0.719.
• Modafinil 200mg + D-Amphetamine 30mg + Therapy: mean 6.00 versus 4.91 on control; difference 1.09 (95% CI -5.33 to 7.51), standardized effect d = 0.14; z-test p = 0.739.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous, and the registry reports it as a mean with a standard deviation. The mean is the arithmetic average of the individual TES values in an arm. The standard deviation describes variation among those values: a larger standard deviation indicates more dispersion around the group mean. It is not the uncertainty interval for the mean, and it does not imply that every participant’s result was close to the mean.

What does the mean difference represent?

Each comparison is an unadjusted mean difference between an active-treatment group and placebo plus therapy. The difference is oriented as the active group’s mean minus the comparator’s mean. For example, the reported difference for d-amphetamine 60mg plus therapy is 4.34, based on means of 9.25 and 4.91. A positive estimate means the active group’s observed average TES was higher; a negative estimate would mean it was lower. The estimate is a contrast between sample means, not a count of additional negative urines for every participant and not an adjusted treatment effect.

The reported standard deviations are substantial in relation to the group means, which signals considerable variability in the observed scores. In general, high variability makes it harder to estimate a group mean difference precisely, especially when group sizes are limited. The registry does not provide participant-level distributions, so the shape of the TES values and the influence of unusually high or low scores cannot be assessed from these summaries alone.

How should the confidence intervals be understood?

A confidence interval expresses the sampling uncertainty around an estimated difference under the assumptions of the statistical procedure. In general, a wider interval indicates less precision, while a narrower interval indicates greater precision. The intervals reported for all three comparisons include zero. This means that a zero difference is among the values compatible with the interval; it does not prove that the true difference is zero. The intervals also extend to both positive and negative values, so they leave room for effects in either direction.

Confidence intervals are not guarantees about the exact value of a population difference, nor do they describe where most individual participants’ scores fall. They are about uncertainty in the comparison estimate. Their interpretation depends on the analysis assumptions, including how the outcome distribution and observations were handled. The statistical model and any checks of assumptions are not reported in the registry record.

What does a p-value add?

The reported p-values are unadjusted: 0.279, 0.719, and 0.739 for the three respective active-treatment comparisons. In general, a p-value measures how unusual the observed data, or data more extreme, would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. These p-values do not provide evidence of a clear difference under the unadjusted tests, but they do not demonstrate equivalence or rule out potentially relevant differences.

The registry record does not report the exact test or model used for its sponsor analysis, whether any covariates were included, whether assumptions were checked, or whether standard errors were adjusted for any features of the design. The displayed comparisons are unadjusted summaries; no adjusted estimates are reported. In general, adjustment can account for prespecified factors, but it can also change estimates and their uncertainty. Without a reported analysis plan, such details should not be inferred.

Why does variability matter?

In general, over-dispersion means that outcome variation is greater than a model expects. When data are more variable than assumed, standard errors may be too small if the analysis does not accommodate that extra variation, making intervals too narrow and tests too optimistic. Conversely, appropriate methods for the actual distribution can better reflect uncertainty. TES is a count-based measure, but the registry reports means and standard deviations rather than a detailed distribution or a model for count data. It is not possible to determine from the record whether a count model, a normal approximation, or another procedure was used in the original analysis.

The small arm-level endpoint counts and broad spread of observed values make it particularly important to consider the uncertainty around the mean differences. The reported intervals convey substantial uncertainty, but the record does not give enough detail to assess sensitivity to outliers, missing observations, or alternative models. The posted summary statistics allow a basic reading of average differences and precision, not a full reconstruction of the trial’s statistical analysis.

How should the endpoint population be considered?

The stated primary analysis included participants who received the first dose of study medication. This description identifies an analysis population, but it does not establish that the analysis was intention-to-treat. The number randomized, reasons for exclusions, and the handling of participants without endpoint data are not reported in the registry record. It is also not reported whether all randomized participants contributed to the posted outcome summaries.

These distinctions matter because exclusion after randomization or missing outcome values can affect comparability between groups. In general, an analysis that retains participants in their assigned groups can preserve the benefits of randomization, while analyses limited to people with observed outcomes can be vulnerable to bias if missingness is related to outcomes or treatment. The record does not report enough information to determine which concerns apply or how they were addressed.

10. Confidence Intervals and Precision

The mean-difference confidence intervals are broad relative to their point estimates. For d-amphetamine 60mg plus therapy versus placebo plus therapy, the estimate is 4.34 and the interval extends from -3.517 to 12.2. For modafinil 400mg plus therapy, the estimate is 1.18 and the interval extends from -5.248 to 7.608. For the combined medication group, the estimate is 1.09 and the interval extends from -5.333 to 7.513.

All three intervals include zero. They also include negative and positive values, so the data do not pin down the direction of the underlying difference with precision. The estimates are compatible with no difference, as well as with differences favoring either group. The interval endpoints should be considered along with the point estimates rather than relying on the estimates alone.

Precision is limited in part by the modest outcome-group counts and the substantial standard deviations reported for TES. The standard deviations range from 7.56 in the placebo-plus-therapy group to 13.45 in the d-amphetamine 60mg-plus-therapy group. In general, more variable outcomes make group means harder to estimate precisely. The registry does not report the precision of any adjusted model or any alternative analysis.

A confidence interval addresses uncertainty in the mean difference under the analysis assumptions; it does not show the range of individual participant outcomes. Nor does an interval containing zero establish that two treatments are equivalent. The record does not report a clinically important difference threshold, so the practical importance of values within these intervals cannot be judged from the endpoint summaries alone. The widths reinforce that the results are inconclusive about the magnitude and direction of 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 for the pairwise comparisons, not total event counts. They are illustrations based on the observed effect and do not represent the trial’s original enrollment plan. The calculation assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario uses the stated fraction of the observed effect as the effect to detect.

For each comparison, the 80% power column gives the illustrative number of participants per arm under which the calculation would have an 80% chance of detecting the specified effect if that effect were real and the assumptions held. The 90% power column uses a higher target chance of detection under the same conditions. These are planning targets, not guarantees that a study will detect an effect.

The rows describe planning for 100%, 75%, and 50% of the observed effect. For the d-amphetamine comparison, the figures range from 108 participants per arm for 80% power and 144 for 90% power when planning for 100% of the observed effect, to 429 and 574 when planning for 50%. For modafinil 400mg, the corresponding figures range from 692 and 926 to 2,766 and 3,703. For the combined medication comparison, they range from 771 and 1,032 to 3,083 and 4,127.

Smaller effects require more participants to detect under the same assumptions. The displayed figures are not observed power; they are planning illustrations, and they depend strongly on treating the observed effect as a reasonable basis for planning. The original trial’s sample-size justification and design assumptions are not reported in the registry record.

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 = 4.340; pooled standard deviation σ = 11.338.
2. n = 2 × (1.96 + 0.842)² × 11.338² / 4.340² = 107.1, rounded up to 108 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 <- 4.34                      # observed difference in means
sigma <- 11.3378655907471                     # 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(218062)
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 = 108 (80% power), 144 (90% power)
 75% of observed effect: n per arm = 191 (80% power), 255 (90% power)
 50% of observed effect: n per arm = 429 (80% power), 574 (90% power)
power.t.test: 108.1 
Simulated power at n = 108 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 record lists five outcome measures and two posted secondary outcomes: medication compliance by self-report percentage of pills taken, and medication compliance by the percentage of riboflavin-positive urine samples. The primary outcome comparisons include three active-treatment groups against placebo plus therapy. Considering several outcomes or comparisons raises a multiplicity question: if many tests are performed, the chance of obtaining at least one apparently unusual result can increase. In general, multiplicity procedures can control that risk, but may also affect the interpretation and precision of individual comparisons.

The three reported p-values are explicitly unadjusted. The registry record does not report a multiplicity adjustment, a prespecified testing hierarchy, or which outcomes were designated for confirmatory inference. It also does not report whether additional analyses were conducted but not posted. The count of analyses recorded is 0, which does not establish that no statistical analyses were carried out; details of the analysis plan are not reported in the registry record.

Missing outcome data are also important for a urine-based endpoint measured over a treatment period. The registry does not report the number of expected or collected urine samples per participant, how missed samples were handled when calculating TES, whether missingness was imputed, or whether sensitivity analyses were performed. Without these details, the reported mean could reflect different patterns of observation across participants or groups, and the potential effect of missing data cannot be assessed.

The primary endpoint population is described as all participants who received the first dose of study medication. This is not enough to identify the full analysis set or to establish whether participants were analyzed according to randomized assignment. The record does not report group-specific reasons for exclusion, the number randomized to each arm, or whether the endpoint analysis included every randomized participant. These omissions limit assessment of how well randomization was preserved and how representative the posted results are of the randomized population.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events by group, with zero affected participants in each listed group. The numbers at risk were 22 for d-amphetamine 60mg plus therapy, 20 for modafinil 400mg plus therapy, 15 for the combined medication group plus therapy, and 16 for placebo plus therapy. These are safety denominators, not the primary endpoint analysis counts.

A zero in the serious-adverse-event affected column means that no affected participants are listed for that group in the posted record. It does not establish that no unrecorded event occurred, nor does it show that the groups have identical safety profiles. The registry record does not provide serious adverse event terms for these groups.

For other adverse events, the affected counts were 1 for d-amphetamine 60mg plus therapy, 3 for modafinil 400mg plus therapy, 2 for the combined medication group plus therapy, and 0 for placebo plus therapy. These are counts of affected participants as reported, not rates calculated. Deaths are not reported in the registry record. The posted safety figures should be interpreted with the stated at-risk counts and the limited detail available; they do not support conclusions about comparative safety.

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

The posted results describe average TES values during 16 weeks of treatment in the analyzed groups. The observed mean was higher for each active-treatment group than for placebo plus therapy, with mean differences of 4.34, 1.18, and 1.09 for d-amphetamine 60mg, modafinil 400mg, and the combined medication group, respectively. The confidence intervals for all three comparisons include zero and extend in both directions. The data therefore leave substantial uncertainty about the true differences.

These findings do not establish that any regimen is effective or ineffective. A non-small unadjusted p-value does not prove there is no difference, and a positive point estimate does not prove a benefit. The record does not provide a clinically important difference threshold, an equivalence framework, or a complete statistical analysis plan with which to interpret the estimates against a decision threshold.

The endpoint captures the total number of cocaine-negative urine samples during treatment. It does not summarize every dimension of participants’ health or treatment experience. Interpretation is also constrained by unreported details about urine collection, missing samples, the analysis model, and the composition of the analysis population. The trial’s enrollment and outcome-group counts should not be conflated: the primary analysis was described as including people who received the first dose, and arm-level endpoint counts are reported separately.

The results are best read as estimates with considerable uncertainty from a phase 2 randomized study, not as definitive evidence about outcomes in other settings or populations. The registry record supplies descriptive group data and unadjusted comparisons, but does not report enough detail to resolve concerns about multiplicity, missing data, or the trial’s original statistical design assumptions.

16. Why This Trial Matters Statistically

This trial illustrates why an estimated difference should be interpreted together with its uncertainty. The active-treatment group means were higher than the placebo-plus-therapy mean, but all three confidence intervals span zero and include values in either direction. A reader who focuses only on the point estimates would miss the limited precision; a reader who focuses only on the unadjusted p-values could mistake a lack of strong evidence for proof of equivalence.

The outcome also highlights the distinction between a repeated measurement and a participant-level summary. TES combines cocaine-negative urine samples over a treatment period into a total count. The reported mean and standard deviation convey the average and spread of that summary, but do not reveal when samples were missed, whether observations were clustered over time, or how individual patterns differed. Those features can matter for analysis, yet the registry record does not report them.

The safety reporting offers another statistical lesson: denominators for adverse-event summaries differ from the arm-level endpoint counts. They answer a separate question and should not be substituted for the analysis population used for TES. The record also shows why an absence of reported serious affected participants should be described narrowly, rather than turned into a broad safety conclusion.

Finally, planning calculations based on an observed effect are sensitive to the effect selected for future study. The planning illustrations grow substantially as the assumed target effect becomes smaller. They demonstrate the connection between effect size, variability, and sample size, but cannot explain the original enrollment decision because the trial’s own design assumptions are not reported.

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 posted primary endpoint comparisons involve limited arm-level outcome counts, and the reported standard deviations are large relative to the group means. The resulting confidence intervals are wide and include zero. This limits precision and leaves uncertainty about both the direction and size of the underlying differences.

The registry record does not report the original sample-size justification, the randomization method, allocation concealment, or the details of who was masked. It does not report the sponsor’s full statistical analysis plan, the model used for the primary analysis, whether any covariates were adjusted for, or how the model assumptions were assessed. The unadjusted comparisons therefore cannot be taken as a complete account of the trial’s analysis.

Important information about the endpoint is also not reported in the registry record. This includes the schedule and collection of urine samples, the treatment of missed samples in the TES calculation, the extent of missing outcome data, and any sensitivity analyses. The record identifies the primary analysis population as participants who received the first dose, but does not report the full randomized population, reasons for exclusion, or whether all randomized participants contributed to the outcome estimates.

The registry lists multiple outcomes and posts two secondary outcomes, while the primary comparisons have unadjusted p-values. A prespecified multiplicity strategy is not reported. Safety information is limited to affected counts and at-risk denominators; detailed serious adverse event terms are absent, and deaths are not reported in the registry record. These limitations make it difficult to judge the robustness, completeness, and broader interpretation of the posted results.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Effectiveness of Modafinil and D-amphetamine in Treating Cocaine Dependent Individuals — NCT00218062.
• Registry record last updated 2017-06-21; status last verified 2017-05.
• Results first posted 2017-06-21.
• 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

NCT00218062 is a completed phase 2 randomized, quadruple-masked, parallel-group study sponsored by The University of Texas Health Science Center, Houston. The registry lists enrollment of 73, a study start of 2006-03, and primary completion in 2012-01.

The primary outcome was TES, the total number of cocaine-negative urine samples during 16 weeks of treatment. The posted comparisons of d-amphetamine 60mg, modafinil 400mg, and their listed combination with placebo plus therapy show positive mean differences, but all confidence intervals include zero and are broad. The registry record does not report key details of the original statistical plan, missing-data handling, or sample-size justification.