Role of Proinflammatory Signaling in Alcohol Craving: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Role of Proinflammatory Signaling in Alcohol Craving (NCT01631630), a randomized phase 2 study. The primary outcome is Alcohol Craving in Response to the Alcohol Cue Script.

2. Clinical Question

3. Trial Design

This randomized phase 2 trial compared pioglitazone with placebo in a parallel-group design. The registry describes the study as triple-masked and reports enrollment of 16 participants. Its status is terminated; the reason for termination is not reported in the registry record. The sponsor was the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

The registry summary describes inpatient treatment at the National Institutes of Health Clinical Center for 5 weeks, with standard treatment for alcoholism during the stay. Participants were assigned to pioglitazone or placebo. The pioglitazone schedule began at 15mg/day for 3 days, increased to 30mg/day for 3 days, and then continued at 45mg/day, for a minimum total of 13 days. The placebo group followed a similar schedule, also for a minimum total of 13 days.

The study included personalized scripts involving stressful, alcohol-related, and neutral events, as well as questionnaires and imaging studies related to mood and craving. The posted primary analysis concerns the response to the alcohol cue script. Its specified measurement time was 15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period.

The analysis population was narrower than enrollment: the registry says that only subjects completing all three script types were included. The posted primary outcome has 6 participants in the pioglitazone group and 8 in the placebo group. Reasons that participants did not contribute to the primary analysis are not reported in the registry record. Further details about allocation procedures, the masking arrangements, and the reason for termination are also not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The analyses included only those subjects who completed all three script types (neutral, alcohol, stress)

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 Alcohol Craving in Response to the Alcohol Cue Script, measured over 15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period.

The primary endpoint is alcohol craving in response to an alcohol cue script, measured with the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered measure of current craving: it asks about craving in the present context. Its score ranges from 8, the lowest craving value, to 56, the highest craving value. The reported unit is units on a scale.

The endpoint was assessed 15 minutes prior to the beginning of script presentation on Day 21, 22, or 23 of the treatment period. The primary outcome title refers specifically to the alcohol cue script. The primary analysis population included only participants who completed all three script types: neutral, alcohol, and stress. The registry does not report why completion of all three scripts was required for inclusion.

In general, a measure focused on the response to an alcohol-related cue can describe craving in a defined context rather than general craving over time. The AUQ's current-context framing is relevant to interpreting its scores: they represent reported craving at the assessment, not a direct measure of future drinking or longer-term outcomes. The posted result is a least-squares mean for each group, with standard error as the accompanying dispersion measure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry labels the primary outcome quantity as a least-squares mean and the dispersion as standard error. A least-squares mean is generally a model-based estimate of a group mean. It may account for terms in an analysis model, whereas a raw arithmetic mean is calculated directly from the observed values. The model terms and estimation details for this endpoint are not reported in the registry record, so the degree and nature of any adjustment cannot be assessed.

Standard error describes uncertainty in an estimated mean. It is not the same as the standard deviation, which describes variation among individual observations. A smaller standard error generally indicates a more precisely estimated mean, but precision depends on the analysis and the available data. The two reported standard errors do not provide the uncertainty for the difference between groups. That requires an estimate of the contrast and its variance, neither of which is posted for the primary outcome.

A confidence interval would give a range of values compatible with the data under the method used, while conveying uncertainty around an estimate. No confidence interval for the primary group means or their contrast is reported. The registry also lists 0 analyses for this continuous endpoint and gives a reason that values were missing or not estimable for a two-arm comparison. Thus, there is no posted inferential result for comparing the groups. The separate arm estimates remain descriptive rather than a formal test of the treatment contrast.

In general, an inferential comparison needs to specify how the observations are combined, what assumptions are made, and how uncertainty is estimated. The registry does not report the statistical model, covariates, variance assumptions, or handling of repeated measurements for the primary analysis. Although the trial included different script types, the posted primary outcome concerns alcohol-cue craving and the population is restricted to those who completed all three script types. It is not reported how script completion or the timing options were handled analytically.

The distinction between the trial's enrollment and the primary analysis population matters. Enrollment was 16, whereas the primary outcome lists 6 participants in one group and 8 in the other. The record does not describe the disposition of participants between enrollment and analysis, or whether missing outcome data were imputed, excluded, or handled by another method. There is therefore no basis to characterize the result as an intention-to-treat estimate. The registry's stated restriction to completers should be kept in mind when interpreting the arm means.

What does over-dispersion mean in general?

In general, over-dispersion means that observed variability is greater than a model assumes. It can make standard errors too small if the model does not account for that extra variability. This issue is especially relevant to some count-data models; the posted primary endpoint is continuous and the registry does not report a model or an assessment of over-dispersion. It should not be assumed to have occurred in this trial.

How should planning illustrations be read?

Sample-size planning illustrations based on an observed effect are hypothetical planning calculations, not observed power. The registry describes the illustrations as using a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect set to a stated fraction of the observed effect. Such illustrations depend on assumptions about the effect to detect and the analysis. They do not show the probability that this completed trial detected an effect, and they are not a substitute for a reported treatment contrast and its uncertainty. The planning calculations are not the trial's own design justification; that justification is not reported in the registry record.

In general, a prespecified analysis plan helps clarify which outcome, population, and statistical method are primary, and how secondary outcomes and missing data are handled. The statistical plan, sample-size justification, interim analyses, and multiplicity strategy are not reported in the registry record. Consequently, the posted group means can be described, but the registry record does not support a more detailed reconstruction of the intended inferential analysis.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Pioglitazone", "Placebo")
n   <- c(6, 8)
m   <- c(13.7505, 8.1871)
sp  <- c(2.3136, 1.9853)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Pioglitazone  6  13.751  5.667  7.803  19.698
CARM  Placebo  8  8.187  5.615  3.493  12.882

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and many secondary outcome measures; 30 secondary outcomes are posted. Repeated entries for anxiety symptom ratings appear in the registered outcome list. The number of outcome measures and the number of posted secondary outcomes indicate that interpretation extends beyond a single measurement, but the registry does not report a multiplicity strategy. It is therefore not clear whether any formal adjustment was planned for testing multiple outcomes, time points, or comparisons.

Multiplicity matters in general because conducting many statistical tests can increase the chance of finding at least one apparently notable result by chance. Without a reported testing hierarchy or adjustment method, secondary findings should be treated as exploratory rather than as a set of independently confirmed effects. No inferential analysis is posted for the primary continuous comparison, and the registry lists 0 analyses for that endpoint.

The primary analysis included only participants who completed all three script types. Enrollment was 16, while the two reported primary groups contain 6 and 8 participants. The registry does not report why other enrolled participants were not included, whether missingness differed by group, or how missing data were handled. It also does not report whether the analysis population was defined before the results were examined. These omissions limit assessment of selection bias and the applicability of the primary estimates to all randomized participants.

In general, missing-data methods can affect estimates when participants with unavailable outcomes differ from those with observed outcomes. No imputation method, sensitivity analysis, or intention-to-treat analysis is reported in the registry record. The impact of missing data cannot be determined from the posted information.

12. 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: abnormal glucose (12.5%), elevated creatine kinase (12.5%).

The registry reports serious adverse events among 8 participants at risk in each group. Serious adverse events affected 2 participants in the pioglitazone group and 0 in the placebo group. The record lists abnormal glucose and elevated creatine kinase as the leading serious-event terms, each reported at 12.5%. It does not specify in the posted summary which treatment group is associated with each term, so those terms should not be assigned to a particular group.

Other adverse events affected 8 of 8 participants at risk in the pioglitazone group and 7 of 8 in the placebo group. These are counts of participants with one or more reported events, not counts of all event episodes. The registry does not provide enough detail in these figures to determine severity, duration, relationship to study treatment, or whether the same participant experienced multiple event types.

Deaths are not reported in the registry record. A count of serious events is a descriptive safety result and is not, by itself, evidence that an event was caused by the assigned treatment. With the small numbers at risk and the lack of a posted comparative safety analysis, the group counts should be read as a record of reported events rather than a precise estimate of relative safety.

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

The posted result gives group-level AUQ estimates for alcohol-cue craving in the participants who completed all three script types. The pioglitazone estimate is 13.75, with a standard error of 2.314, among 6 participants. The placebo estimate is 8.187, with a standard error of 1.985, among 8 participants. The AUQ measures current craving, and higher values indicate higher craving on its scale.

These estimates do not establish that pioglitazone caused a change in craving. The registry does not post a confidence interval, p-value, or other inferential comparison for the primary outcome. The observed group means alone do not quantify uncertainty around the treatment contrast. A formal interpretation of that contrast would require the comparison method and its uncertainty, which are not reported.

The result also does not answer whether treatment changes drinking behavior, longer-term craving, or other clinical outcomes. The primary assessment is tied to an alcohol cue script at a specified point in the treatment period. Its findings apply directly to that measurement context and to the analyzed completer subset, not automatically to all participants or to outcomes outside the trial's reported measures.

The registry's terminated status and the difference between enrollment and the analyzed group sizes add uncertainty about how the available data came to be reported. The reason for termination and the reasons for missing primary outcome data are not reported in the registry record. These gaps make it difficult to judge how representative the analyzed participants are of the randomized population.

The appropriate conclusion is therefore descriptive: the registry reports distinct average AUQ values in the two analyzed groups, with standard errors attached to each mean, but does not provide a formal test or interval for the treatment comparison. The figures neither demonstrate a reliable treatment effect nor rule one out.

14. Why This Trial Matters Statistically

This trial is statistically instructive because it separates a posted outcome estimate from a complete inferential result. Least-squares means and standard errors can summarize group data, but they are not enough to reconstruct a treatment comparison when the model, contrast, and uncertainty for that contrast are absent. Readers can describe the group values while avoiding claims that the registry does not support.

The analysis population also matters. The study enrolled 16 participants, but the primary outcome includes only those who completed all three script types, with 6 in the pioglitazone group and 8 in the placebo group. That restriction is relevant to both precision and potential selection: the analyzed set may not represent everyone randomized. Because reasons for non-inclusion and missing-data methods are not reported, the direction or size of any resulting bias cannot be assessed.

The endpoint has a clearly described measurement context: current alcohol craving assessed with the AUQ in response to an alcohol cue script. This specificity helps define what the score represents and what it does not. It is not a direct measure of drinking or a broad measure of long-term outcomes. Statistical interpretation depends on respecting that scope as well as the limits of the analysis.

Finally, many secondary outcomes are posted, but the registry does not describe how multiplicity was managed. That omission makes it important to distinguish an exploratory pattern from a prespecified confirmatory finding. The record illustrates why estimates, analysis populations, missingness, and testing plans all matter alongside a numerical result.

15. 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 outcome is based on a small analyzed population: 6 participants assigned to pioglitazone and 8 assigned to placebo. The registry reports enrollment of 16 but does not explain why the remaining enrolled participants are absent from the primary analysis. Since inclusion required completion of neutral, alcohol, and stress scripts, the result may reflect a selected subset. The extent or direction of any selection effect cannot be determined.

No inferential comparison is posted for the primary outcome. The registry provides least-squares means and standard errors but not a contrast estimate, confidence interval, or p-value. The analysis model, any adjustment variables, and the method used to handle repeated or incomplete measurements are not reported in the registry record. As a result, uncertainty around the difference between groups cannot be assessed from the posted primary values.

The registry status is terminated, but the reason for termination is not reported. It is also not reported whether the study stopped as planned, whether all outcomes were collected as intended, or whether the termination affected the available sample. The statistical analysis plan, sample-size justification, and interim analyses are not reported in the registry record.

The primary assessment concerns current craving in response to an alcohol cue script at a defined treatment-period time. The registry result does not establish effects on drinking or longer-term outcomes. The number of registered and posted secondary outcomes raises questions about multiplicity, but no correction or testing hierarchy is described. These limitations constrain both causal interpretation and generalization from the analyzed participants.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Role of Proinflammatory Signaling in Alcohol Craving — NCT01631630.
• Registry record last updated 2017-03-09; status last verified 2017-01.
• Results first posted 2016-12-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01631630, titled “Role of Proinflammatory Signaling in Alcohol Craving,” is a randomized, triple-masked, parallel-group phase 2 trial sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Enrollment was 16, and the registry status is terminated. The reason for termination is not reported in the registry record.

The trial compared pioglitazone with placebo during an inpatient study described as lasting 5 weeks. The primary outcome was alcohol craving measured by the AUQ in response to an alcohol cue script. The posted least-squares means are 13.75 for 6 participants receiving pioglitazone and 8.187 for 8 receiving placebo; the corresponding standard errors are 2.314 and 1.985.

The analysis included participants who completed all three script types. No inferential comparison for the primary continuous outcome is posted, and missing-data methods, the statistical plan, and the reasons for the reduced analysis population are not reported in the registry record. The results should therefore be read as descriptive group estimates with important uncertainty about the comparison.