Imaging Extrastriatal Dopamine Release in Tobacco Smokers and Nonsmokers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Imaging Extrastriatal Dopamine Release in Tobacco Smokers and Nonsmokers (NCT02348385), a registered phase not stated study. The primary outcome is Percent Change in Binding Potential of Dopamine Release During PET Scan Post Amphetamine Administration.

2. Clinical Question

The study goal is to examine sex differences in amphetamine-induced dopamine release in tobacco smokers and nonsmokers. The listed primary outcome is a continuous PET measure: percent change in binding potential after amphetamine. Binding potential is described as a proxy for the availability of dopamine D2/3 receptors in a region of interest.

The record describes a single arm in which all participants receive amphetamine, while also labeling groups as Healthy Tobacco Smokers and Healthy Nonsmokers. Those labels distinguish smoking status; they do not establish that one group is an untreated control. Allocation is not stated, and the record cautions that the groups are not a like-for-like control comparison.

The endpoint results by smoking status, sex, or any other subgroup are not reported in the registry record. Nor are sex-specific estimates or a statistical comparison of those estimates reported. The clinical question can therefore be described from the study objective and endpoint, but the posted results do not allow assessment of the size, direction, or precision of any difference.

3. Trial Design

This completed study, NCT02348385, is titled “Imaging Extrastriatal Dopamine Release in Tobacco Smokers and Nonsmokers.” Yale University is listed as the sponsor. The registry record gives a start date of 2012-12 and a primary completion date of 2017-12, and reports enrollment of 49 participants. Nicotine dependence is the listed condition.

The intervention is amphetamine. The group descriptions are Healthy Tobacco Smokers and Healthy Nonsmokers, and both descriptions state that all subjects receive amphetamine. The record also says there is only one arm. Thus, the group labels should not be read as evidence of a randomized treatment-versus-control design. Allocation is not stated, and the registry record explicitly cautions that this is not a randomized, like-for-like control comparison.

The primary outcome is percent change in binding potential of dopamine release during a PET scan after amphetamine administration. Its timeframe is after 2 PET scans (1 day). The outcome is specified as a mean with standard deviation, indicating a continuous endpoint summarized by a group mean and a measure of dispersion.

The registry record lists one outcome measure and no analyses. It does not report a protocol-level statistical analysis plan, assignment procedures, a sample-size justification for the study, or the number contributing data to the primary endpoint. The stated status is COMPLETED, but completion status alone does not establish that all planned analyses or results are available in the registry record. Numerical endpoint estimates and inferential results are 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

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 Percent Change in Binding Potential of Dopamine Release During PET Scan Post Amphetamine Administration, measured over After 2 PET Scans (1 day).

The primary endpoint is percent change in binding potential during PET imaging after amphetamine administration. Binding potential is defined in the registry record as a PET neuroimaging outcome measure computed as a proxy for the availability of dopamine D2/3 receptors in a region of interest. The measure is therefore an imaging-based proxy, not a direct count of dopamine molecules or a direct measure of receptor number.

Expressing the change as a percentage describes the outcome relative to the binding-potential measurement used as its reference. In general, a percent-change endpoint can make changes interpretable relative to a baseline level, although the registry record does not specify the calculation details or which scan supplies the reference value. The listed timeframe is after 2 PET scans (1 day), but further timing and processing details are not reported in the registry record.

The study objective concerns sex differences in amphetamine-induced dopamine release among smokers and nonsmokers. The endpoint could be used to compare the imaging response across sex or smoking-status groups if suitable estimates and analysis details were reported. The registry record does not report those estimates or comparisons. It also does not report the regions of interest used, the endpoint distribution, or the number of participants contributing measurements. The endpoint’s definition explains what was intended to be measured, but does not itself establish the observed response or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous and is designated as a mean with standard deviation. In general, a mean describes the central value of observations, while a standard deviation describes how dispersed individual observations are around that mean. These summaries answer different questions: the mean describes the average outcome, whereas the standard deviation describes variability among observations. Neither quantity is reported for this endpoint in the registry record, so the observed average and participant-level spread cannot be assessed.

A mean is often useful when a continuous measure is being summarized, but its interpretation depends on the measurement and analysis population. For a percent-change endpoint, the mean would describe the average percent change among participants included in the analysis. The registry record does not report the number included, whether all enrolled participants contributed data, or how missing scans or measurements were handled. The posted endpoint description therefore does not reveal whether the analysis used all enrolled participants or a subset.

What would a confidence interval add?

General explanation: a confidence interval expresses statistical uncertainty around an estimate under a specified analysis method. A narrower interval indicates greater precision than a wider interval, but precision is not the same as importance. An interval also does not remove design limitations, measurement error, or the possibility of bias. No confidence interval for the primary endpoint is reported in the registry record, and no analysis method for producing one is stated.

What does the design allow researchers to compare?

The registry record describes one arm and says all subjects receive amphetamine, while identifying smokers and nonsmokers as groups. It does not state that participants were randomized to amphetamine or to a control condition. In general, random allocation can help make treatment groups comparable with respect to measured and unmeasured characteristics; without it, observed group differences may reflect factors other than the intervention. Here, the record itself cautions that the groups are not a like-for-like control comparison. A contrast between smoking-status groups should therefore not be interpreted as a randomized treatment effect.

The stated aim concerns sex differences, but the registry record does not report a sex-specific analysis. In general, an analysis of effect differences across groups requires an estimate for each group and an appropriate comparison of those estimates. Separate group descriptions or participant counts do not establish that such an analysis was performed. The registry lists no analyses, so there is no reported test, model, or estimate to interpret.

How should the planning assumptions be read?

The record describes a sample-size 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 states that the effect to detect is a stated fraction of the observed effect. Such calculations are planning illustrations, not evidence about the probability that this completed study detected an effect. They are not observed power. The numerical planning results are not reported in the registry record, and the record does not report the trial’s own sample-size justification.

General explanation: a significance level is a threshold used in a specified testing procedure, while a normal approximation uses a mathematical model to estimate sampling behavior. Equal allocation is an assumption about how participants are divided between comparison groups. These assumptions do not establish that the actual study used that allocation, test, or model; the registry record does not report the statistical analysis plan or allocation method. The planning assumptions should not be mistaken for documented analysis procedures.

Why can variability matter?

General explanation: when data are more variable than a model assumes, standard errors and confidence intervals may be too small if the model does not account for that extra variability. Over-dispersion is one name for variability greater than expected under a chosen model. The endpoint is continuous and is described with a mean and standard deviation, but no distributional assessment, model, or over-dispersion finding is reported in the registry record. It would therefore be inappropriate to claim that over-dispersion occurred or that a particular adjustment was used.

Several further details needed for a full statistical appraisal are not reported in the registry record: the precise percent-change calculation, region-of-interest definitions, analysis population, handling of missing measurements, any covariate adjustment, and any sensitivity analysis. Without numerical endpoint results and these analysis details, the endpoint’s magnitude, precision, and robustness cannot be evaluated from the registry entry.

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("Male Healthy Tobacco Smokers", "Male Healthy Nonsmokers", "Female Healthy Tobacco Smokers", "Female Healthy Nonsmokers")
n   <- c(12, 13, 12, 12)
m   <- c(14, 11.2, 1.9, 9.3)
sp  <- c(4.3, 2.4, 3, 3.3)
sd  <- sp      # posted standard deviations
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  Male Healthy Tobacco Smokers  12  14.000  4.300  11.268  16.732
CARM  Male Healthy Nonsmokers  13  11.200  2.400  9.750  12.650
CARM  Female Healthy Tobacco Smokers  12  1.900  3.000  -0.006  3.806
CARM  Female Healthy Nonsmokers  12  9.300  3.300  7.203  11.397

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure, the primary percent change in binding potential, and lists no analyses. This describes what is entered in the registry; it does not establish whether researchers considered additional outcomes, subgroups, or exploratory comparisons outside the posted record. A multiplicity plan, including how any multiple tests were handled, is not reported in the registry record.

The study objective mentions sex differences and the groups are labeled by smoking status, so analyses across sex or smoking-status groups may be relevant to the research question. However, the registry record does not report subgroup estimates, tests, or a prespecified hierarchy of comparisons. It is therefore not possible to determine which comparisons were planned, whether any were exploratory, or how multiplicity might affect their interpretation.

Enrollment of 49 is reported, but the endpoint analysis population and the number with complete PET measurements are not reported in the registry record. Missing-data frequency, reasons for missingness, exclusions, imputation, and sensitivity analyses are also not reported. In general, missing outcomes can affect an estimate if participants with observed data differ from those without observed data. Without the missing-data details, the direction or scale of any such effect cannot be assessed.

The registry record does not identify an intention-to-treat, per-protocol, or other analysis population for the primary endpoint. It also does not report a statistical analysis plan. Consequently, it is not possible to establish how the analysis population was defined or whether it matched a prespecified plan. These omissions matter for interpreting both the representativeness of the endpoint estimate and the credibility of any subgroup comparison.

12. 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 record reports serious adverse events and other adverse events separately for Healthy Tobacco Smokers and Healthy Nonsmokers. Among the 24 smokers at risk, 0 serious adverse events and 0 other adverse events are recorded. Among the 25 nonsmokers at risk, 0 serious adverse events and 0 other adverse events are recorded. Deaths are recorded as 0 in both groups.

These figures are counts in the registry record, not evidence that no adverse experience of any kind occurred. They describe the listed serious and other adverse-event categories for the stated at-risk groups. The record does not provide event-term details for non-serious events, and the list of top serious terms is empty. The event ascertainment methods, observation period for safety, and completeness of adverse-event reporting are not reported in the registry record.

The safety counts should not be used as a substitute for the primary PET endpoint results. Nor do they establish a randomized safety comparison: both group descriptions state that participants receive amphetamine, and the record cautions that the groups are not a like-for-like control comparison. The figures are best read narrowly as the adverse-event counts posted for these two labeled groups.

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

The registry record describes a completed study intended to examine sex differences in amphetamine-induced dopamine release among tobacco smokers and nonsmokers. It specifies a PET-based primary endpoint: percent change in binding potential after amphetamine administration. Binding potential is described as a proxy for dopamine D2/3 receptor availability in a region of interest. These details explain the study question and measurement, but the record does not provide the numerical endpoint findings.

Without a reported mean, standard deviation, confidence interval, or test result, the magnitude and precision of the endpoint response cannot be evaluated. No conclusion about the direction of change, differences by sex, or differences by smoking status is supported by the posted results. The absence of numerical results in the registry record is not evidence that the study found no effect; it means the outcome is not available there for statistical interpretation.

The design description also matters. All subjects are stated to receive amphetamine, and the record describes only one arm while labeling smoker and nonsmoker groups. Allocation is not stated, and the record cautions against treating the groups as a like-for-like control comparison. Thus, the group labels do not establish a randomized contrast or an untreated reference group.

The sample-size planning assumptions are not study findings. A planning illustration based on an observed effect does not reveal observed power, prove that the study was adequately sized, or establish that an effect was detected. The resulting numerical illustrations are not reported in the registry record. The posted safety counts indicate zero recorded serious and other adverse events in each labeled group, but do not provide a complete account of safety ascertainment.

Overall, the registry record supports a precise description of the intended PET endpoint and major design caveats. It does not support a conclusion about the observed endpoint effect, its uncertainty, or whether the study objective was met.

14. Why This Trial Matters Statistically

This study raises statistical issues that are common in imaging research: how a proxy measure is defined, how repeated scans are used to characterize change, and how group comparisons are interpreted when treatment exposure is shared. The primary endpoint is a continuous percent change in binding potential, with binding potential serving as a proxy for dopamine D2/3 receptor availability. Clear distinction between the imaging proxy and the biological process it is intended to represent is important when interpreting any eventual estimate.

The design descriptions require particular care. The registry record names smokers and nonsmokers but says there is only one arm and that all participants receive amphetamine. It does not state allocation and explicitly cautions that this is not a randomized, like-for-like control comparison. Statistical contrasts between these groups, if performed, would need to be interpreted as group associations rather than automatically as causal treatment effects.

The study objective centers on sex differences, but no sex-specific estimates or analyses are reported. This highlights the distinction between a stated scientific question and a posted analysis capable of answering it. To assess a group difference, readers need estimates, uncertainty, and an analysis description; subgroup labels alone are not enough.

The entry also illustrates why reporting completeness is part of statistical interpretation. Enrollment and safety counts are available, yet the primary endpoint values, analysis population, missing-data handling, and statistical methods are not reported in the registry record. Without them, readers cannot judge precision, robustness, or whether the reported participant count corresponds to the analyzed PET data. These limitations constrain what can be learned from the record, even though the study is marked completed.

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 most consequential limitation for interpreting the posted results is that no numerical primary endpoint results are reported in the registry record. The endpoint is defined, but its mean, standard deviation, uncertainty, and any inferential comparison are absent. As a result, the size and direction of the PET outcome cannot be assessed.

The registry record says the study has only one arm and that all subjects receive amphetamine, while presenting Healthy Tobacco Smokers and Healthy Nonsmokers as group labels. Allocation is not stated, and the record cautions that the groups are not a like-for-like control comparison. This limits causal interpretation and makes it inappropriate to treat either group as a randomized control for the other.

The research objective names sex differences, but sex-specific results and analysis details are not reported. The record also does not report the number of participants contributing endpoint data, the analysis population, missing measurements, or how exclusions were handled. Enrollment of 49 should not be assumed to equal the endpoint analysis sample.

Technical details needed to understand the imaging endpoint are not reported in the registry record, including the exact percent-change calculation and region-of-interest definitions. A statistical analysis plan, model specification, covariate handling, and sensitivity analyses are also not reported. The sample-size illustration assumptions do not replace a trial-specific design justification or document the analysis actually performed.

Finally, the safety figures are limited to the event categories and group counts posted in the record. Event ascertainment procedures and safety follow-up details are not reported. These limitations do not show that the study lacked additional methods or findings; they identify information not available in the registry record for evaluating this study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Imaging Extrastriatal Dopamine Release in Tobacco Smokers and Nonsmokers — NCT02348385.
• Registry record last updated 2023-03-02; status last verified 2023-02.
• Results first posted 2020-03-18.
• 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

NCT02348385 is a completed Yale University study titled “Imaging Extrastriatal Dopamine Release in Tobacco Smokers and Nonsmokers.” The registry record reports enrollment of 49 and lists nicotine dependence as the condition. The study goal is to examine sex differences in amphetamine-induced dopamine release in tobacco smokers and nonsmokers.

All subjects are described as receiving amphetamine. The listed groups are Healthy Tobacco Smokers and Healthy Nonsmokers, but the record says there is only one arm, does not state allocation, and cautions that the groups are not a like-for-like control comparison. The primary endpoint is percent change in binding potential during PET imaging after amphetamine administration, after 2 PET scans (1 day).

The registry record lists one outcome measure and no analyses. Numerical endpoint results, sex-specific findings, analysis-population details, and missing-data methods are not reported in the registry record. The posted adverse-event counts are zero for serious events, other events, and deaths in each labeled group.