Endophenotype for Alcohol Misuse in Healthy Minority Populations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Endophenotype for Alcohol Misuse in Healthy Minority Populations (NCT00256451), a randomized phase 4 study. The primary outcome is Biphasic Alcohol Effects Scale - Stimulation.

2. Clinical Question

The research question combines a behavioral response to alcohol with a pharmacologic manipulation. The registry summary says investigators sought to understand relationships among inherited family characteristics, feelings and responses after drinking, and responses after pretreatment with naltrexone. It identifies people of African descent as the study focus. The posted primary endpoint, however, is a stimulation-scale measure; the record does not post genetic results or an analysis linking genetic characteristics to the primary outcome. The clinical question addressed by the posted primary results is therefore narrower than the study’s broader stated motivation: whether mean peak change in stimulation differed across alcohol and sham-alcohol conditions, with active or placebo naltrexone.

The crossover structure means the study was organized around participants attending multiple challenge sessions. The brief summary describes four sessions, separated by at least 10 days. Because the same people may contribute measurements under more than one condition, interpretation of condition contrasts depends on how repeated observations and within-person relationships were handled. That analysis approach is not reported in the registry record. The posted arm-level summaries and recalculated contrasts can describe the observed pattern, but they do not by themselves establish how a crossover-specific analysis would estimate the condition effects.

3. Trial Design

The registry identifies this as a Phase 4, randomized, quadruple-masked, crossover study. It records the status as completed and enrollment as 43. The listed start and primary-completion dates are 2005-11 and 2008-05. The brief summary says the investigators sought to enroll 40 people and describes four alcohol-challenge sessions, with each session separated by at least 10 days. A sequence-generation method, allocation concealment procedure, and details of how masking was maintained are not reported in the registry record.

The four listed conditions combine two factors: alcohol versus sham alcohol, and active naltrexone versus placebo naltrexone. They are alcohol with active naltrexone, sham alcohol with active naltrexone, alcohol with placebo naltrexone, and sham alcohol with placebo naltrexone. This factorial arrangement allows descriptive contrasts that vary the alcohol challenge while holding the naltrexone condition fixed, or vary the naltrexone condition while holding the challenge fixed. The posted primary comparisons use sham alcohol with active naltrexone as the reference. The registry does not report the order in which participants received conditions, whether order was randomized, or whether period or carryover effects were modeled.

The primary outcome was measured during challenge sessions and is described as change from baseline to peak in stimulation after alcohol ingestion. The registry also lists sedation and fatigue as secondary outcomes. It identifies the primary measure as a continuous mean with standard deviation. The reported sample sizes differ across conditions, but the record does not explain why they differ or how incomplete observations were handled.

The record does not report the original sample-size calculation, its assumed effect size, its target power, or its planned significance level. It also does not report a detailed analysis plan, an interim-analysis plan, the analysis population, or how the crossover structure was incorporated into a model. The listed masking and randomization labels describe broad design characteristics; they do not provide enough detail to reconstruct the conduct or statistical analysis of the study. The registry record’s status is completed, but completion alone does not establish that every planned participant or session contributed to every outcome.

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: Participants were only randomized to 4 sequences and not to all 12 possible sequences.

Session1

Session2

Session3

Session4

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 Biphasic Alcohol Effects Scale - Stimulation, measured over During challenge sessions.

The primary endpoint is the Biphasic Alcohol Effects Scale – Stimulation, expressed in units on a scale. It measures the change from baseline to the peak feeling of stimulation after alcohol ingestion during challenge sessions. The scale sums seven items, each rated on an 11-point Likert scale from 0, not at all, to 10, extremely. Its possible range is 0 to 70, and higher scores are defined in the registry as a worse outcome.

Using change from baseline to peak focuses the measure on the response occurring during the challenge rather than simply describing a score at one time. The peak is intended to capture the strongest reported stimulation during a session, while the baseline comparison expresses the response relative to the participant’s starting level. This makes the measure relevant to the study’s stated interest in how people respond and feel after drinking alcohol and whether that response differs with naltrexone pretreatment.

The registry gives the endpoint timeframe as during challenge sessions and reports means and standard deviations for the conditions. It does not describe the exact timing or frequency of measurements used to identify the peak, how baseline was defined, or how missing measurements affected peak calculation. It also does not provide a clinically meaningful threshold for a difference on this scale. Consequently, the means and contrasts describe the magnitude and direction of the posted scale values, but the record alone does not establish what size of change would be important to participants or clinically meaningful.

7. Results Posted in the Registry

• ALC and NAL: mean 11.30 versus 3.90 on control; difference 7.40 (95% CI 3.87 to 10.93), standardized effect d = 0.92; z-test p = <0.001.
• Placebo Pill and ALC: mean 8.70 versus 3.90 on control; difference 4.80 (95% CI 1.92 to 7.68), standardized effect d = 0.74; z-test p = 0.001.
• Placebo Pill and Placebo ALC: mean 3.20 versus 3.90 on control; difference -0.70 (95% CI -2.88 to 1.48), standardized effect d = -0.14; z-test p = 0.530.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Biphasic Alcohol Effects Scale - Sedation

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • ALC and NAL: mean 14.80 versus 13.40 on control; difference 1.40 (95% CI -5.25 to 8.05), standardized effect d = 0.09; z-test p = 0.680.
  • Placebo Pill and ALC: mean 15.90 versus 13.40 on control; difference 2.50 (95% CI -4.63 to 9.63), standardized effect d = 0.16; z-test p = 0.492.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between ALC and NAL and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Placebo Pill and ALC and the control. The interval gives the range of effects that remain compatible with the data.

Profile of Mood States - Fatigue Scale

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • ALC and NAL: mean 2.20 versus 1.60 on control; difference 0.60 (95% CI -0.19 to 1.39), standardized effect d = 0.33; z-test p = 0.136.
  • Placebo Pill and ALC: mean 2.00 versus 1.60 on control; difference 0.40 (95% CI -0.27 to 1.07), standardized effect d = 0.27; z-test p = 0.243.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between ALC and NAL and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Placebo Pill and ALC and the control. The interval gives the range of effects that remain compatible with the data.

The two posted secondary outcomes assess sedation and fatigue, which complement the primary stimulation measure by describing other reported effects during the challenge sessions. Across these outcomes, the posted condition means do not show the same clear separation from the reference that appears in the primary stimulation contrasts. The recalculated intervals for the reported secondary comparisons span zero, and their unadjusted p-values do not indicate strong evidence of a difference under the individual comparisons. This overall pattern is consistent with the primary result being more distinct on stimulation than on the two additional measures, rather than showing a uniform shift across all reported experience scales.

The secondary outcomes relate to the primary result by broadening the description of subjective responses during the alcohol challenge. Stimulation, sedation, and fatigue are distinct scales, and a pattern in one does not entail the same pattern in another. The registry provides no reported analyses tying the secondary scales to the primary response or explaining whether they were intended to support a common mechanism. Their results should therefore be interpreted as separate outcome summaries, not as confirmation or refutation of the primary contrast.

The secondary comparisons carry less inferential weight because they are unadjusted and are considered alongside multiple outcomes and condition contrasts. When many comparisons are examined, the chance of observing an apparently notable result somewhere among them can increase. A prespecified hierarchy or multiplicity adjustment can address that issue, but neither is reported in the registry record. The available results also do not include sponsor-reported analyses for these outcomes.

These secondary measures are not a substitute for a primary endpoint analysis, and they do not directly answer the genetic questions motivating the study. The registry lists five outcome measures overall, while results are posted for the primary measure and two secondary measures. The record does not explain the status of the other outcome measures or whether their results were collected, analyzed, or omitted. That absence limits any claim about the complete pattern of outcomes considered by the investigators.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Biphasic Alcohol Effects Scale - Sedation
• Profile of Mood States - Fatigue Scale

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant’s stimulation response is represented by a scale score, and the registry reports a mean and standard deviation for each condition. A mean difference expresses the contrast between two condition means in the original scale units. Positive differences in the reported alcohol contrasts indicate a higher mean score in the alcohol condition than in the reference condition; the negative difference for the placebo-pill and sham-alcohol contrast indicates a lower mean. Keeping the contrast in scale units makes it easier to relate the estimate to the scale’s range than a standardized measure would.

The posted comparison estimates are unadjusted recalculations from summary statistics. They are not identified in the registry as results from a sponsor-reported statistical model. The registry lists no reported analyses. That distinction matters: a calculation based on means, standard deviations, and condition sample sizes may be useful for a simple comparison, but the calculation does not document the study’s prespecified method or model the crossover structure unless that method is explicitly built into the analysis. The analysis plan and the way repeated measurements were handled are not reported in the registry record.

A confidence interval describes a range of values that are reasonably compatible with the estimate under the assumptions of the method used to construct it. A narrow interval indicates more precision than a wide interval, while an interval spanning zero does not exclude a zero difference at the interval’s stated confidence level. The registry record does not state the confidence level for the displayed intervals. They should therefore be described as reported intervals rather than assigned a confidence level not documented in the record. An interval is not a guarantee that the true value lies inside it, and its interpretation depends on the statistical method and assumptions.

A p-value describes how unusual data at least as incompatible with a null hypothesis would be under the null and the test assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. The posted p-values are unadjusted. The record does not specify the test procedure, whether it was prespecified, or how p-values across endpoints and condition comparisons were addressed. Therefore, a small unadjusted p-value is evidence about that individual comparison under its method, but it does not resolve the broader multiplicity or crossover-analysis questions.

The standard deviation describes the spread of individual observations around a mean. It is different from the standard error, which represents the precision of an estimated mean. The posted outcome summaries give standard deviations, while the recalculated comparisons use summary information to form estimates and intervals. A larger standard deviation indicates more variation among observed scores; it does not imply that the mean is necessarily less meaningful, and it should not be mistaken for the uncertainty interval around the mean difference.

The crossover design is an important consideration. In a crossover study, the same participant can contribute responses under multiple conditions. Observations from one person may be related, so an analysis that accounts for within-person pairing can differ from a comparison that treats the condition summaries as independent. Session order, period effects, and carryover from a prior challenge may also matter. The registry record says the design was crossover and describes repeated challenge sessions, but it does not state whether the posted contrasts use paired observations, whether a repeated-measures model was fitted, or whether order and period were included. The recalculated summaries should not be assumed to answer those design questions.

Over-dispersion is a concept most relevant to count data: it occurs when the variability is greater than a model expects, and ignoring it can make uncertainty estimates too optimistic. The primary endpoint is continuous rather than a count, so count-data over-dispersion is not the central issue for these means. General statistical principle: for continuous outcomes, the distribution and dependence structure still matter. The registry does not describe a distributional model, residual checks, or a method for handling potential dependence among repeated session measurements.

The sample-size planning displays are illustrations based on the observed effect and stated planning assumptions, not the trial’s original design calculation. They use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects set to stated fractions of the observed effect. For continuous outcomes, the displayed figures are participants per arm. The original study’s sample-size justification and assumptions are not reported in the registry record. Planning illustrations can show how requirements change under selected assumptions, but they do not replace a documented protocol calculation or account automatically for the crossover design.

Unadjusted means and contrasts are accessible summaries, but they may not capture all aspects of the study design. An adjusted analysis might account for baseline, participant, session, period, or sequence characteristics, depending on the planned model. General statistical principle: adjustment can address measured design features when specified and implemented appropriately, but it cannot be inferred from a set of summary means. The registry record does not identify such an adjusted analysis, so no particular adjustment should be attributed to the posted results.

What does an unadjusted contrast answer?

It gives the difference between the posted condition means without documented adjustment for other variables or for repeated-session structure. It can describe the observed condition pattern, but it does not establish that all design features were handled. In a crossover study, the distinction between a simple summary contrast and a within-person treatment contrast is especially relevant. The record does not provide enough detail to determine whether the displayed recalculations reproduce an intended crossover estimand.

What does statistical significance add?

A p-value gives a test-based measure of incompatibility with a null comparison, subject to the test assumptions. It does not tell how likely a result is to replicate, whether a score difference matters to participants, or whether unreported design features would change the estimate. When multiple outcomes and contrasts are considered, unadjusted p-values also do not by themselves control the chance of at least one false-positive finding across the set.

11. Confidence Intervals and Precision

The primary alcohol-plus-active-naltrexone contrast with sham alcohol plus active naltrexone is 7.4 units, with a reported interval from 3.875 to 10.93. The alcohol-plus-placebo-naltrexone contrast with the same reference is 4.8 units, with an interval from 1.916 to 7.684. Both intervals are above zero. The placebo-pill and sham-alcohol contrast is -0.7, with an interval from -2.884 to 1.484; it spans zero. These intervals communicate uncertainty around the unadjusted contrast estimates and show that the primary comparisons do not all have the same degree or direction of separation from zero.

The interval endpoints should be considered alongside the point estimates. The point estimate is the single best estimate produced by the calculation, while the interval represents a range of values compatible with the data and method. Greater width indicates less precision. The registry does not report the confidence level or the exact interval method, so the endpoints should not be labeled with a confidence percentage or treated as a complete account of uncertainty. Their validity also depends on assumptions about the observations and analysis.

Precision is limited by the number of observed outcome measurements and by the variability in the scores. The primary condition summaries include 38.0 to 40.0 observations per condition, and the standard deviations differ across conditions. Because this is a crossover study, precision may also depend on the within-person association across sessions. Arm-level counts and standard deviations alone do not show that association. Without the analysis method and paired data, it is not possible to determine from the registry record how much the intervals reflect crossover pairing.

An interval that includes zero does not prove there is no difference. It indicates that the reported range includes zero under the interval method. Conversely, an interval that excludes zero does not establish clinical importance, eliminate bias, or resolve multiplicity. The registry does not give a clinically important difference threshold for the stimulation scale. Precision should therefore be considered separately from the practical meaning of the score difference and from the limitations of the reported analysis.

12. 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 expressed as participants per arm, not total events. These are continuous-outcome planning illustrations; the event-count convention for time-to-event outcomes does not apply to this study. Each figure describes the number of participants per arm under the listed assumptions, rather than the number recruited for the four-condition crossover design. The registry record does not report the original sample-size calculation for this trial.

The illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They use the observed effect as a starting point and also show planning for 75% of the observed effect and 50% of the observed effect. The 80% power column describes the per-arm size that the planning calculation associates with an 80% chance of detecting the specified effect under those assumptions. The 90% power column uses a higher target chance of detecting that effect, so it generally requires more participants per arm.

For example, the primary contrast between alcohol with active naltrexone and sham alcohol with active naltrexone has planning figures of 19 participants per arm for 80% power and 25 participants per arm for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, the figures are 34 and 45; for 50%, they are 75 and 100. The pattern illustrates that smaller target effects require more participants to detect under the same planning assumptions. The other contrasts have their own estimates and corresponding planning figures.

These calculations are not observed power. They are forward-looking illustrations based on effect sizes estimated from the posted results, so they depend on those estimates and on the stated assumptions. They should not be read as evidence that the completed study had a particular probability of finding its results, or as proof that the original enrollment was adequate. The trial’s own design assumptions, target power, and sample-size justification are not reported in the registry record.

13. 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 = 7.400; pooled standard deviation σ = 8.063.
2. n = 2 × (1.96 + 0.842)² × 8.063² / 7.400² = 18.6, rounded up to 19 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 <- 7.4                      # observed difference in means
sigma <- 8.0628778981205                     # 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(256451)
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 = 19 (80% power), 25 (90% power)
 75% of observed effect: n per arm = 34 (80% power), 45 (90% power)
 50% of observed effect: n per arm = 75 (80% power), 100 (90% power)
power.t.test: 19.6 
Simulated power at n = 19 per arm: 0.785 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and secondary outcomes, with results posted for the primary stimulation scale and two secondary scales. It also records five outcome measures overall. Considering several measures and multiple condition contrasts creates a multiplicity issue: even when each individual test uses a conventional threshold, the chance of at least one apparently positive finding across a set of tests can be greater than for a single prespecified test. This is a general statistical concern, not evidence that any particular posted result is false.

The registry record does not report whether the investigators specified a testing hierarchy, adjusted p-values for multiple comparisons, designated secondary outcomes as exploratory, or controlled a family-wise error rate. The posted p-values are unadjusted. They should be interpreted as results for individual comparisons rather than as a multiplicity-controlled conclusion across all outcomes and contrasts. No correction should be assumed.

The record lists no sponsor-reported analyses. It does not report the statistical analysis plan, the model used for the crossover design, or whether the displayed mean contrasts were planned before data collection. It is therefore not possible to determine whether those contrasts were primary protocol analyses, exploratory comparisons, or simple recalculations from posted summaries. The original analysis strategy and its handling of repeated observations are not reported in the registry record.

Missing-data procedures and analysis populations are also not reported. The condition-specific outcome counts are 38.0, 40.0, and 39.0 in the primary summaries, depending on condition. The record does not explain the differences among those denominators, say whether they reflect missing sessions or another reason, or describe any imputation or exclusion rules. Enrollment of 43 does not by itself establish how many participants completed every session or contributed to each outcome. The analysis population—such as whether all randomized participants or only participants with complete session data were included—is not reported.

For a crossover trial, missingness in one session can affect whether a participant contributes to a paired contrast. The registry does not state whether participants with incomplete sequences were included in any model, how partial data were handled, or whether missingness was assessed. Without these details, the posted denominators and summaries cannot resolve possible selection or missing-data effects. These reporting gaps do not demonstrate that the analysis was inappropriate; they mean that its key methods cannot be evaluated from the registry record.

15. 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 zero serious adverse events affecting participants in each of the four conditions. The numbers at risk were 40 in alcohol with active naltrexone, 38 in sham alcohol with active naltrexone, 39 in alcohol with placebo naltrexone, and 38 in placebo-pill and sham-alcohol. The record also reports zero other adverse events affecting participants in each condition, and zero deaths in each condition.

These figures describe the adverse-event counts posted in the registry record. They do not establish that no symptoms or events of any kind occurred, because the posted categories and the record’s reporting definitions determine what is counted. The record does not provide event terms for the serious-adverse-event category, and it does not list serious adverse-event terms. It also does not report detailed timing, duration, severity, or attribution information for adverse events.

Counts of zero should be read in the context of the number of participants at risk and the study’s challenge-session setting. They do not establish the absence of risk or characterize uncommon events reliably. The registry record’s adverse-event counts are a description of what was reported for this study, not a basis for broader safety conclusions.

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

The posted primary results show that mean stimulation change was higher in the two alcohol conditions than in the sham-alcohol condition with active naltrexone. The unadjusted contrasts are 7.4 units for alcohol with active naltrexone and 4.8 units for alcohol with placebo naltrexone, each compared with the active-naltrexone sham-alcohol reference. The placebo-pill and sham-alcohol mean was close to the reference mean, and its contrast interval includes zero. These statements describe the reported scale values and calculated contrasts in this challenge study.

The results do not, by themselves, establish a causal effect of alcohol or naltrexone under a crossover analysis. Randomization and masking are recorded design features, but the registry does not provide the sequence details, crossover-specific model, or analysis plan needed to evaluate how the repeated-session design was handled. The posted unadjusted calculations do not document adjustment for period, sequence, baseline, or possible carryover. The record also does not provide a clinically meaningful threshold for the stimulation scale, so statistical separation should not be equated with a meaningful benefit or harm.

The results do not show whether naltrexone changes alcohol response in a population receiving treatment for alcoholism. The study is described as a challenge experiment in healthy participants and its population focus is people of African descent. Its findings should not be generalized from this record to other populations, clinical settings, or treatment decisions. No medical advice follows from these registry summaries.

The study’s broader stated purpose involved genetics, alcohol response, and pretreatment with naltrexone. The posted results concern stimulation, sedation, and fatigue scales; the registry record does not include genetic outcome results or analyses connecting inherited characteristics to response. Accordingly, the stimulation findings do not answer the full genetic research question. They offer a limited description of selected subjective outcomes across the four challenge conditions, with uncertainty and analysis details that should remain explicit.

17. Why This Trial Matters Statistically

This trial is statistically notable because its design and its posted summaries do not align neatly with the simplest two-group comparison framework. The registry describes a randomized crossover study with four challenge conditions and repeated sessions. In that setting, the same participant may contribute information under several conditions, making within-person dependence potentially important. A summary comparison that does not disclose how that dependence was handled can be informative about the observed means while leaving uncertainty about the intended crossover estimand.

The four conditions also combine alcohol versus sham alcohol with active versus placebo naltrexone. That structure supports several possible comparisons, but the reference used in the posted contrasts is sham alcohol with active naltrexone. The contrasts answer different descriptive questions depending on which condition changes. Clear specification of the comparison and reference is essential: a difference between alcohol and sham alcohol under active naltrexone is not the same question as a difference between active and placebo naltrexone under alcohol.

The endpoint highlights another useful statistical distinction. A scale can have a directional definition—in this case, higher scores are worse—while a numerical difference still lacks a documented clinical-importance threshold. Statistical evidence, precision, and practical meaning are related but separate considerations. Intervals and unadjusted p-values help describe uncertainty in the contrasts; they do not settle the scale’s clinical meaning or the effects of unreported analysis choices.

Finally, the registry’s missing analysis details are themselves relevant to statistical interpretation. The completed status and posted summaries provide valuable descriptive information, but the record does not report the sample-size justification, analysis population, missing-data procedures, multiplicity strategy, or detailed crossover model. Recognizing those boundaries helps readers distinguish what the results directly describe from what would require a fuller protocol or analysis report.

18. Limitations

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

Several limitations arise from the way the study is described and reported. The population is described as healthy and focused on people of African descent, which makes the results specific to that research context. The registry does not give detailed participant characteristics, so the degree to which the enrolled group represents broader populations cannot be assessed from this record. The four-session challenge arrangement is described, but session order, sequence allocation, and carryover handling are not reported.

The primary contrasts are unadjusted recalculations from posted summary statistics, and no sponsor-reported analyses are listed. The record does not report whether the calculations account for within-person correlations in the crossover design. It also does not provide the analysis plan or confidence level and method for the displayed intervals. This limits assessment of whether the posted estimates match the intended statistical analysis.

The reported condition denominators vary, and the registry does not explain why. Missing-data rules, analysis populations, participant flow by session, and the handling of incomplete crossover sequences are not reported. Without those details, it is not possible to assess how incomplete outcomes may affect the summaries.

Multiplicity is another limitation: multiple outcome measures and comparisons are considered, but no adjustment or testing hierarchy is reported. The registry does not give a clinically meaningful difference threshold for the primary scale, and the broader genetic aims are not addressed in the posted outcome results. Finally, the sample-size planning illustrations use observed effects and general assumptions; they do not document the original study justification or establish whether the completed design had adequate precision for effects of interest.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Endophenotype for Alcohol Misuse in Healthy Minority Populations — NCT00256451.
• Registry record last updated 2019-08-21; status last verified 2019-08.
• Results first posted 2019-08-21.
• 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.

22. Record Summary

NCT00256451 is a completed Phase 4 randomized, quadruple-masked crossover study titled “Endophenotype for Alcohol Misuse in Healthy Minority Populations.” The registry records enrollment of 43 and describes four alcohol-challenge sessions in healthy people of African descent. Conditions combined alcohol or sham alcohol with active or placebo naltrexone.

The primary outcome was change from baseline to peak in stimulation during challenge sessions. Posted means were higher in both alcohol conditions than in the sham-alcohol condition with active naltrexone; the unadjusted contrasts were 7.4 and 4.8 units. The placebo-pill and sham-alcohol contrast was -0.7. Two secondary outcomes, sedation and fatigue, were also posted.

The registry record does not report sponsor analyses, the original sample-size justification, the crossover analysis model, multiplicity procedures, or missing-data methods. The posted estimates therefore describe the condition summaries and unadjusted contrasts, with important analysis details unavailable in the record.