Neurobiology of Alcohol and Nicotine Co-Addiction: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Neurobiology of Alcohol and Nicotine Co-Addiction (NCT03338933), a registered phase not stated study. The primary outcome is Brain Activation During Functional Magnetic Resonance Imaging (fMRI) in Response to a Stress Modulated Cue Induced Craving Task (DSNBACK).

2. Clinical Question

The study addresses the neurobiology of recovery from Alcohol Use Disorder among people who use alcohol and nicotine. Its central measurement is task-related brain activation, rather than a clinical recovery endpoint. The task presents a sequence of letters with drug-related or neutral images and asks participants to identify matches occurring N steps earlier. The contrast of interest is activation in the 2-back condition relative to the 0-back condition.

The registry record describes four groups: controls, participants with Nicotine Use Disorder, participants with Alcohol Use Disorder, and participants meeting criteria for both disorders. The alcohol-related group descriptions include at least 8 heavy drinking episodes in the past month and an alcohol-free period from 2 to 4 weeks. The nicotine group is described as current smokers, with at least 10 cigarettes per day; the combined group is also described as current smokers. These are group eligibility descriptions, not evidence that groups were randomized or otherwise made comparable.

The primary question is therefore descriptive and comparative: how does task-related brain activation vary among these substance-use groups at baseline? The registry record does not report the group means, variability, estimated differences, confidence intervals, or test results. It is not possible to determine the direction, size, or precision of any between-group difference from the registered information.

3. Trial Design

The study, titled Neurobiology of Alcohol and Nicotine Co-Addiction, is listed as completed. The registry record gives an enrollment of 109 and identifies the VA Office of Research and Development as the sponsor. The listed start date is 2018-02-08, and the primary completion date is 2023-01-03. Those dates describe the registered study timeline; they do not establish when particular participants were assessed or how long any individual was followed.

Four groups are described: Control Group, Nicotine Group, Alcohol Group, and Nicotine and Alcohol Group. The definitions distinguish participants by histories of substance-use disorders, current smoking, recent heavy drinking, and abstinence. The control group is described as having no history of addiction to any substance or gambling and fewer than 20 lifetime cigarettes or equivalent. The Nicotine Group is described as meeting DSM-V criteria for Nicotine Use Disorder, currently smoking at least 10 cigarettes per day, and having no history of addiction to another substance. The Alcohol Group and the combined group are described as meeting criteria for Alcohol Use Disorder; the combined group also meets criteria for Nicotine Use Disorder. Both alcohol-related groups have the stated recent heavy-drinking and abstinence criteria.

Allocation is not stated in the registry record. The record therefore does not support describing the groups as randomized treatment arms, and it cautions that they are not a like-for-like control comparison. The MRI entry is labeled behavioral, but the registry description does not identify MRI as a therapeutic intervention. Rather, MRI is the context for the brain-activation assessment.

The primary outcome is a continuous measure: mean percent signal change during a baseline fMRI task. The record states that participants could be removed from the primary outcome analysis for excessive motion, incorrect task performance, or not performing the task during the MRI session. It does not report how many participants were excluded for these reasons, the number analyzed in each group for the primary outcome, or the handling of missing measurements.

The registry record lists four outcome measures and no statistical analyses. It does not report a detailed statistical analysis plan, a sample-size justification for the study, or a planned approach to group comparisons. The planning illustration described in the record is not the trial’s own design and should not be mistaken for evidence about the study’s observed analysis or statistical power.

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: Of 616 phone screens conducted at the VA Portland Health Care System, 171 were eligible to participate in the study, and 109 participants signed an informed consent form. 4 participants were screened out or declined participation after consent but prior to any data collection and are not included in participant flow table. Control and Nicotine group's participation was complete after baseline measurements were collected. Alcohol groups continued to next periods.

Screening Visit

Reasons for not completing this period:

Baseline Visit

Check-In Visit (Alcohol Groups Only)

Reasons for not completing this period:

Follow-up Visit (Alcohol Groups Only)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants were removed from analysis due to too much motion, performing the task incorrectly, or did not perform the task during the MRI session.

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.

Population: Participants who screened out or were lost to follow up during the screening visit are not included in baseline analysis population reporting.

6. Primary Endpoint

The registry lists the primary outcome as Brain Activation During Functional Magnetic Resonance Imaging (fMRI) in Response to a Stress Modulated Cue Induced Craving Task (DSNBACK), measured over Baseline.

The primary endpoint is mean brain activation, expressed as percent signal change, during a baseline functional MRI assessment. The task is the DSN-back, a cognitive task intended to assess working memory and attention. Participants view letters on a screen alongside either drug-related or neutral images and identify matches separated by a specified number of steps. The registered contrast compares the higher-demand 2-back condition with the lower-demand 0-back condition.

This contrast is used to examine task-specific neural activation under differing working-memory demands. The endpoint description notes that inconsistent activation patterns across regions may be relevant to neural processing involved in cognitive control, emotion regulation, and reward processing. It also explains that values closer to 0 in regions such as the Amygdala and ACC may indicate reduced task-specific engagement, where drug-related processes may be dominating neural activity. These statements describe the rationale for the measure; they are not reported findings from this study.

Because the endpoint is continuous, a group result would ordinarily be described using a mean and a measure of variation, such as the standard deviation. The registry identifies the mean and standard deviation as the summary measure and dispersion measure. However, it does not report the actual values by group, estimates of differences, confidence intervals, or test results. The endpoint’s definition alone therefore cannot show whether activation differed between groups or how precisely any difference was estimated.

The outcome is recorded at baseline. It is a task-based brain-activation measure, not a direct measure of recovery, substance use after assessment, or clinical benefit. The registry record does not report a longitudinal change in this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a continuous primary outcome summarized by a mean, with standard deviation as the measure of dispersion. A mean represents the average observed value in a group. A standard deviation describes how spread out individual values are around that group’s mean. These summaries can help characterize the distribution of a continuous outcome, but they do not by themselves quantify uncertainty in a comparison between groups. The record does not report the group means or standard deviations for the primary endpoint.

What would a group comparison estimate?

A comparative analysis would need to define the groups being contrasted and the quantity being estimated. For a continuous measure such as percent signal change, an unadjusted comparison could describe how far apart group means are. An adjusted analysis could instead estimate a contrast after accounting for selected participant characteristics. The registry record does not report the actual contrasts, a model, adjustment variables, or an analysis plan. No comparison should be inferred from the endpoint description alone.

The group definitions matter for interpretation. The registry describes distinct eligibility criteria for controls, nicotine use, alcohol use, and combined nicotine and alcohol use. It does not state that participants were allocated at random. Random allocation and observational classification have different implications: randomization, when used and properly implemented, can balance participant characteristics on average across assigned groups, while classification by existing status does not itself ensure such balance. This is a general statistical distinction, not a claim about analyses performed in this study. The registry warns that the groups are not a like-for-like control comparison.

How should uncertainty be read?

A confidence interval is a statistical summary of uncertainty around an estimated quantity. In general, it shows a range of values that are reasonably compatible with the data and the method used to calculate the interval. A narrow interval indicates greater precision than a wide interval, but precision is not the same as clinical or scientific importance. A confidence interval for a group contrast would help readers assess both the possible size and the uncertainty of that contrast. No confidence intervals are reported for the primary endpoint in the registry record.

A p-value, when reported, summarizes how incompatible the observed data are with a specified null model, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of an effect. The registry’s planning illustration specifies a two-sided significance level of 0.05, but the primary outcome’s p-value is not reported. A planning threshold should not be mistaken for an observed result.

What does the planning illustration mean?

The record describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also states that the effect to detect is a stated fraction of the observed effect. These assumptions define an illustrative calculation; they do not describe the study’s own design or establish its achieved power. The illustration is not a substitute for a reported analysis.

In general, power is the probability that a specified statistical procedure will identify an effect of a particular size under stated assumptions. A calculation using an effect estimated from observed data is sensitive to the uncertainty in that estimate and should not be read as observed power. Sample-size calculations are planning illustrations, not results about the study’s ability to detect an effect. The registry record does not report the underlying primary outcome estimates needed to evaluate such illustrations independently.

The record’s general planning assumptions also distinguish between participants per arm and total events for time-to-event outcomes. The primary endpoint is continuous, not time-to-event. The registry does not report a time-to-event primary outcome. No sample-size figure or event total should be inferred from those general instructions.

Why can motion and task performance matter?

Functional MRI measurements can be affected by movement and by whether participants complete the task as intended. The registry explicitly identifies excessive motion, incorrect task performance, and failure to perform during the MRI session as reasons for removal from the primary outcome analysis. This makes the analysis population important: if the participants included differ systematically from those excluded, the analyzed measurements may not represent everyone enrolled. The record does not report exclusion counts, reasons by group, or a comparison of included and excluded participants.

Missing-data methods describe how analyses handle outcome values that are unavailable. General approaches can include analyzing only participants with observed measurements, imputing missing values under specified assumptions, or using models that accommodate incomplete observations. These approaches rely on different assumptions and can yield different results. The registry record does not say which approach was used, whether any imputation was conducted, or whether sensitivity analyses were performed.

Finally, a statistical analysis requires more than an endpoint definition. It also requires clarity about the population analyzed, the contrast of interest, the model, assumptions, handling of missingness, and the treatment of multiple outcomes or comparisons. The registry identifies four outcome measures but lists no statistical analyses. Those methodological details are not reported in the registry record, so the primary outcome’s estimate and uncertainty cannot be evaluated.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures and no statistical analyses. It does not report which measures were designated primary or secondary beyond identifying the brain-activation measure as primary. It also does not report how many group contrasts were planned, whether multiple regions of the brain were tested, or whether any correction for multiple comparisons was used.

Multiplicity arises when several outcomes, groups, regions, or statistical tests are considered. In general, conducting many tests can increase the chance of observing at least one apparently notable result by chance. Statistical approaches to address multiplicity can adjust significance thresholds or control a specified error rate, but the appropriate approach depends on the analysis goals and structure. No multiplicity strategy is reported in the registry record, so it is not possible to assess how multiple outcomes or comparisons were handled.

The primary outcome description specifies that participants were removed from analysis for excessive motion, incorrect task performance, or not performing the task during MRI. The record does not state how many participants were affected, whether the exclusions differed across groups, or how missing outcome values were handled. It does not identify the number analyzed for the primary endpoint or say whether all other outcome analyses used the same population.

Analysis populations can be defined in different ways, depending on the study design and question. The registry does not describe an intention-to-treat population, a per-protocol population, or another formal analysis set. Since allocation is not stated and the groups are not a like-for-like control comparison, no particular population framework should be assumed. The details needed to judge selection, missingness, and multiplicity are not reported in the registry record.

11. 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’s safety entries report serious adverse events, other adverse events, and deaths separately for each group. For the Control Group, 31 participants were listed as at risk for serious events and 31 for other events; the corresponding affected counts were 0 and 0, and deaths were 0. For the Nicotine Group, the at-risk counts were 28 for serious events and 28 for other events; the affected counts were 0 and 0, and deaths were 0. For the Alcohol Group, the at-risk counts were 13 and 13; the affected counts were 0 and 0, and deaths were 0. For the Nicotine and Alcohol Group, the at-risk counts were 33 and 33; the affected counts were 0 and 0, and deaths were 0.

These are the counts entered in the registry record. A zero affected count means no events were recorded in that category for the listed group; it does not establish that the underlying risk is zero. Event counts can be informative, but their interpretation depends on the observation period, event definitions, completeness of reporting, and the number of participants assessed. The registry record does not provide further detail about these aspects or list serious-event terms.

The safety counts should not be confused with the number of participants analyzed for the fMRI endpoint. The outcome analysis had separate stated removal criteria, and the record does not report the primary endpoint analysis population by group. The safety listings also do not answer the study’s brain-activation question.

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

The study’s registered objective concerns the neurobiology of recovery from Alcohol Use Disorder among alcohol and nicotine users. Its primary measure is baseline task-related brain activation in a working-memory fMRI task. The registry provides the endpoint definition, group descriptions, and reasons participants could be removed from the primary outcome analysis. These details clarify what the study was intended to investigate.

However, the registry record does not report the primary endpoint values or statistical comparisons. There is no reported group mean, standard deviation, estimated contrast, confidence interval, or p-value for the outcome. As a result, the posted information does not establish whether activation differed between any groups, the direction or size of a possible difference, or how precise an estimate might be. It also does not establish a relationship between the measured activation and recovery outcomes.

The group descriptions should not be read as randomized treatment assignments. Allocation is not stated, and the record cautions that the arms are not a like-for-like control comparison. Group differences, if estimated, could reflect differences in the participant characteristics used to define the groups or other unreported factors. The registry does not give an adjustment strategy that would allow those issues to be assessed.

The outcome is a task-based measure of brain activation rather than a direct clinical endpoint. The registry’s explanation of why the measure may be relevant is a rationale, not a finding. It does not show that any activation pattern occurred in the participants or that a particular pattern predicts a clinical outcome.

The completion status and enrollment figure do not substitute for outcome results. Nor do the zero adverse-event counts establish the primary outcome or answer the comparative question. The most defensible conclusion is that the registry record describes a completed study and a measurable baseline fMRI endpoint, but does not report the analyses required to determine what the study found about that endpoint.

13. Why This Trial Matters Statistically

This study is statistically interesting because it uses a continuous, task-based brain measure to investigate groups defined by alcohol and nicotine use. It brings together a specific fMRI contrast, 2-back relative to 0-back, and a question about neural activity during working-memory demands. Such a measure can be informative for neuroscience research, but interpreting it requires clear reporting of both the observed values and the analysis that connects those values to the research question.

The four group definitions make the comparison structure important. The groups differ by substance-use history and current or recent behavior, and the registry does not state that allocation was random. The record explicitly warns that the groups are not a like-for-like control comparison. Statistical interpretation therefore depends not only on calculating a contrast, but also on understanding how participants entered each group and whether relevant differences were considered in analysis. The registry does not report the model or adjustment variables.

The primary endpoint also illustrates why analysis populations matter in imaging studies. The record identifies motion and task performance as reasons for exclusion. Those rules may affect which measurements are usable, but the number of exclusions and their distribution across groups are not reported. Without this information, readers cannot assess how the analyzed participants relate to those enrolled.

Finally, this record shows the distinction between a registered question and a reported answer. The study is marked completed, and it specifies the endpoint and group criteria, but no statistical analyses or primary outcome results are reported. A well-defined measure is necessary for interpretation, yet it cannot establish an effect without estimates and uncertainty. For biostatisticians and clinical researchers, the missing analysis details are consequential: they prevent evaluation of the observed group pattern, its precision, and the robustness of any conclusion.

14. 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 limitation for interpreting this study from the registry record is that outcome results are not reported. There are no group-specific means or standard deviations for the primary fMRI measure and no reported statistical contrasts, confidence intervals, or p-values. The direction, magnitude, and precision of any group differences are therefore unknown from the registry.

The record lists an enrollment of 109, but does not report the number contributing primary outcome data in each group. It names excessive motion, incorrect task performance, and failure to perform the task during MRI as reasons for removing participants from the primary analysis. Exclusion counts and missing-data handling are not reported in the registry record. This leaves uncertainty about the size and composition of the analysis population.

Allocation is not stated, and the record cautions that the groups are not a like-for-like control comparison. The group definitions reflect different substance-use histories and behaviors. The registry does not report whether potential differences between groups were adjusted for, which factors were considered, or how any adjusted comparison was specified.

The statistical analysis information is limited: the registry lists four outcome measures but no statistical analyses. It does not report the number of planned group contrasts, the approach to multiple comparisons, model assumptions, or sensitivity analyses. The primary outcome is measured at baseline, and the record does not report a longitudinal endpoint for assessing change over time.

Finally, the registry’s safety listings report zero affected counts and deaths for the listed groups, but do not provide additional detail about event definitions or observation. These counts do not address the primary outcome. Taken together, the record identifies the research question and measurement approach but does not contain the results or methodological detail needed for a full statistical appraisal.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Neurobiology of Alcohol and Nicotine Co-Addiction — NCT03338933.
• Registry record last updated 2025-02-13; status last verified 2025-02.
• Results first posted 2025-02-13.
• 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.

18. Record Summary

NCT03338933, Neurobiology of Alcohol and Nicotine Co-Addiction, is listed as completed and sponsored by the VA Office of Research and Development. The registry record gives an enrollment of 109, a start date of 2018-02-08, and a primary completion date of 2023-01-03.

The study describes Control, Nicotine, Alcohol, and Nicotine and Alcohol groups. Its primary outcome is mean percent signal change during baseline fMRI, comparing the 2-back with the 0-back condition of the DSN-back task. The record notes that excessive motion, incorrect task performance, or not performing the task during MRI could lead to removal from the primary outcome analysis.

The registry lists four outcome measures and no statistical analyses. It does not report primary outcome values, group comparisons, confidence intervals, or p-values. Allocation is not stated, and the record cautions that the groups are not a like-for-like control comparison. The registered information defines the study question and measurement, but does not report the results needed to assess group differences.