Nicotine Withdrawal Symptoms and Smoking Relapse: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nicotine Withdrawal Symptoms and Smoking Relapse (NCT01511614), a randomized na study. The primary outcome is BOLD Activation in Right ACC During Parametric Flanker Task tDCS Stimulation.

2. Clinical Question

The study’s broader purpose was to investigate nicotine withdrawal symptoms and brain function in smokers after 36 hours without smoking. The brief description frames withdrawal symptoms as relevant to early relapse, while the listed primary endpoint is a brain-imaging outcome during tDCS or sham stimulation. These are related topics in the registry description, but the endpoint does not itself quantify relapse or establish whether withdrawal symptoms changed.

Because the record does not identify a single comparison or provide primary outcome values, it cannot establish the direction or size of a difference between stimulation conditions. The endpoint description names several task conditions and stimulation conditions, but does not report which of these formed the primary statistical test. The clinical question is therefore clear at the level of the measured brain signal, but not at the level of a specific estimand or contrast.

3. Trial Design

The registry describes a randomized, double-masked, crossover study with an enrollment of 112. The study is marked completed. Its listed start date is 2013-05-20, and its primary completion date is 2020-03-30. The phase is recorded as NA. The sponsor is the National Institute on Drug Abuse (NIDA).

The brief summary describes a study of withdrawal symptoms and brain function during 36 hours of smoking abstinence. It says participants were required to be able to abstain for 36 hours on two occasions and describes nicotine-patch or placebo-patch exposure during abstinence and study visits. The broader record lists interventions that include tDCS and sham, nicotine and placebo patches, varenicline and placebo pills, and motivational interviewing. Arm descriptions distinguish treatment-seeking smokers, smokers not seeking treatment, a motivational-interviewing group, and tDCS groups that include smokers, non-smokers, and a behavioral pilot. These descriptions indicate a broad study structure; they do not provide a complete account of how each group relates to each outcome.

In general, a crossover design measures participants under more than one condition, so within-person comparisons may be possible. Randomization concerns assignment to a sequence or condition, while double masking indicates that masking was used; the identities of the people masked and the detailed sequence are not reported in the registry record. For this primary endpoint, the exact order of conditions, washout arrangements, and analysis of repeated measurements are not reported in the registry record.

The brief description also refers to MRI sessions, blood sampling, EEG, questionnaires, and tasks. The primary outcome is instead specified as right anterior cingulate cortex BOLD percent signal change during a flanker task. The registry record lists 11 outcome measures, but does not report a completed analysis count or a single primary comparison. Enrollment is the stated planned or recorded study enrollment, not a substitute for the number contributing to this particular endpoint; the endpoint-specific analysis population is 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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as BOLD Activation in Right ACC During Parametric Flanker Task tDCS Stimulation, measured over During tDCS or sham stimulation. Day 1 for non-smokers. Day 1 or 2 for smokers (counterbalanced for nicotine condidtion).

The primary endpoint is BOLD percent signal change in the right anterior cingulate cortex (rACC) during a parametric flanker task. BOLD refers to the blood-oxygen-level-dependent MRI signal. The outcome is recorded in percent BOLD change, with the registry specifying a mean and standard deviation as the summary format.

The flanker task varies the relationship between target and surrounding stimuli. The record describes congruent trials, where the flanker stimuli are identical to the target, and medium and high levels of incongruence. In general, a task that varies conflict or response demands can be used to examine brain activity during performance. The rACC is the brain region selected for the reported signal measure; the registry does not state why this region was selected or provide a specific rationale for the endpoint.

The endpoint is assessed during tDCS or sham stimulation. The description names 2mA anodal stimulation at the left dorsolateral prefrontal cortex, 2mA cathodal stimulation at the left dorsolateral prefrontal cortex, and sham. It also identifies timing that differs by group: during stimulation, Day 1 for non-smokers, and Day 1 or 2 for smokers, counterbalanced for nicotine condition. This is not a clinical outcome such as abstinence, smoking relapse, or withdrawal symptom burden. The registry record does not report the endpoint values, a primary contrast, or an effect estimate, so it is not possible to describe the observed size or direction of a difference from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the study as randomized, double-masked, and crossover, but does not provide a statistical analysis plan. The concepts below are general explanations; the analysis details for this particular primary endpoint are not reported in the registry record.

What does a crossover design imply?

In general, a crossover study measures a participant under more than one condition. This can allow a comparison within the same participant, reducing the influence of characteristics that remain stable over the measurement periods. That advantage depends on an appropriate design and analysis. Condition order, period effects, carryover effects, and the handling of repeated observations can affect interpretation. The registry labels this study crossover, but its condition sequence, washout details, and statistical handling of period or carryover effects are not reported in the registry record.

The primary description refers to measurements during tDCS or sham and to more than one task condition. It also describes timing that varies by smoker status and nicotine condition. A statistical analysis would need to specify the contrast of interest and account for the way observations are related within participants, if repeated observations were collected. The exact model and covariance assumptions are not reported in the registry record. The label “crossover” alone does not specify those choices.

What does the endpoint summary represent?

The registry states that the endpoint is a continuous measure summarized by a mean and standard deviation. In general, the mean is an average, while the standard deviation describes variability among measurements. For a comparison, the estimated difference between means is often more informative than either mean alone, because it directly expresses the contrast being studied. A confidence interval around an estimate communicates its precision and the range of values compatible with the data under the model. Neither an estimate nor an interval for the primary endpoint is reported in the registry record.

BOLD percent change is the measured scale, and the selected region is the rACC. The description includes congruent, medium-incongruent, and high-incongruent flanker-task conditions, as well as multiple stimulation conditions. In general, the more conditions and outcome categories included in an analysis, the more important it is to define in advance which contrast answers the primary question. The registry does not report a single contrast, an adjustment approach, or a model for combining the task conditions.

Why do repeated measurements and variability matter?

General statistical principle: measurements from the same participant are often correlated. Treating correlated observations as if they came from unrelated participants can misstate uncertainty. A repeated-measures model or a participant-level analysis may be appropriate, depending on the design and estimand. The method used for this endpoint is not reported in the registry record. The record also does not report whether distributions were checked, whether transformations were considered, or how outlying observations were handled.

Standard deviation describes observed spread; it is not the same as the standard error, which describes uncertainty in an estimated mean under a specified sampling model. A confidence interval typically uses an estimate and its standard error, along with a method suited to the analysis. As no primary estimate or interval is reported, the precision of the endpoint result cannot be assessed from this record.

How should statistical tests and multiplicity be considered?

In general, a p-value summarizes how inconsistent data are with a specified null model, subject to the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not quantify clinical importance. A p-value is meaningful only alongside a defined contrast, an analysis population, and a suitable model. No primary p-value or test is reported in the registry record.

Multiple stimulation conditions, task conditions, time points, and outcome measures can lead to multiple possible tests. Testing several contrasts without a plan can increase the chance of at least one apparently unusual result. Methods such as prespecifying a primary contrast or adjusting for multiple comparisons can address this issue, but the registry does not report whether such methods were used. The record lists 11 outcome measures and indicates that the primary outcome has several categories or time points rather than one reduced comparison. The number of statistical analyses reported is 0.

What do planning illustrations mean?

General principle: a sample-size illustration based on an observed effect is a planning calculation, not a measure of the study’s observed power. It asks what sample size might be needed under stated assumptions to detect an effect of a chosen size. Such a calculation depends on assumptions about the effect, variability, significance level, allocation, and statistical model. The stated assumptions for the planning calculations use a two-sided significance level of 0.05, equal allocation, and a normal approximation; they describe the effect to detect as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed or powered that way. The registry record does not report the trial’s own sample-size justification or the analysis used to estimate the primary endpoint.

Because the primary endpoint spans several categories or time points and is not reduced to one comparison, a planning illustration cannot be read as a direct assessment of the primary study question unless its target contrast and assumptions match that question. The record does not report those details. A planning result should not be interpreted as observed evidence, nor should it be used to infer that a result would or would not be statistically significant.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 11 outcome measures, and it describes the primary outcome across several task categories or time points without reducing it to one comparison. Multiple stimulation conditions, task conditions, and measurement occasions can create several plausible contrasts. In general, testing many contrasts without a prespecified approach can increase the chance of finding at least one nominally unusual result. Prespecifying a primary contrast, using a hierarchical testing plan, or applying an adjustment for multiple comparisons are possible approaches, but whether any was used is not reported in the registry record.

The registry lists 0 analyses. It does not report a primary effect estimate, confidence interval, p-value, or statistical model. It also does not report a protocol-defined analysis population, participant flow into the imaging analysis, missing-data methods, or the extent and pattern of missing endpoint data. These details are important in a crossover study because incomplete measurements may affect which within-participant comparisons can be made. Whether missingness was handled by excluding incomplete cases, imputing values, or another method is not reported in the registry record.

The broad study descriptions distinguish treatment-seeking smokers, smokers not seeking treatment, a motivational-interviewing group, and tDCS groups that include smokers and non-smokers. Which groups contributed to the primary endpoint, and whether analyses were stratified or adjusted by smoking or nicotine condition, are not reported in the registry record. The record also does not report whether interim analyses occurred or whether the analysis plan changed. These gaps limit evaluation of the risk of selective reporting and the robustness of any unreported comparisons.

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.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts of 0 in each listed group, and deaths of 0 in each listed group. For other adverse events, the reported counts are 0 for Main Study - Treatment among 14 at risk; 5 for Main Study - Non-Treatment among 28 at risk; 0 for Main Study - Motivational Interviewing Arm among 2 at risk; 7 for tDCS Arm - Smoker among 32 at risk; 3 for tDCS Arm - Non-Smoker among 33 at risk; and 0 for tDCS Arm - Behavioral Pilot among 3 at risk.

These are group-specific registry counts, not a complete account of all possible harms or a comparison of event rates under randomized conditions. The record does not describe the event terms behind the other-adverse-event counts, their severity, timing, or relationship to an intervention. It also does not report how the safety groups relate to one another or to the full enrollment, so their group sizes should not be combined to infer a total. A zero serious-event count in these listed groups means none were recorded in those groups in this registry entry; it does not establish that serious events are impossible or that the interventions are free of risk.

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

The record establishes that a randomized, double-masked crossover study was completed and that its primary outcome concerned rACC BOLD percent change during a flanker task under tDCS or sham stimulation. It also documents a broader study context involving nicotine withdrawal, smoking abstinence, imaging, and several intervention groups. Those details describe the question and measurement framework, but do not provide a numerical primary result.

Without an estimate for a defined contrast, it is not possible to state whether BOLD activation was higher or lower under one stimulation condition than another, how large any difference was, or how precisely it was estimated. The registry record does not report a confidence interval or p-value for the primary endpoint. It also does not identify one primary comparison among the listed stimulation and task conditions. Therefore, no conclusion about statistical evidence for a specific contrast can be drawn from this record.

Even if a difference in BOLD activation were reported, general interpretation would require attention to the contrast, analysis model, variability, and uncertainty. A statistically detectable difference in a brain-imaging signal would not automatically mean that participants experienced fewer withdrawal symptoms, were less likely to relapse, or changed smoking behavior. Those are distinct outcomes. The primary endpoint is a neural signal measured during a task and stimulation condition, not a direct measure of cessation or relapse.

The safety counts offer a limited description of events recorded in named groups. They do not identify the event types behind the other-adverse-event counts, establish causality, or provide a full benefit-risk assessment. The registry record also does not report the endpoint-specific analysis population or missing-data handling, which are needed to judge how representative the measured results would be if estimates were available.

The appropriate reading is consequently descriptive: the study was completed, its design and primary measurement are identified, and selected safety counts are posted. The registry record does not report enough statistical outcome information to support a claim about the direction, magnitude, precision, or practical importance of a primary effect.

13. Why This Trial Matters Statistically

This study illustrates why the exact endpoint and contrast matter in clinical research. Its broad motivation concerns nicotine withdrawal and early relapse, but its named primary outcome is a brain-imaging signal during a flanker task under stimulation conditions. Keeping those levels distinct prevents a mechanistic measurement from being mistaken for a direct behavioral or clinical outcome.

The crossover label also makes the analysis structure important. General statistical principle: measurements made on the same participant are related, and comparisons should reflect that relationship. Condition order, period effects, and carryover can also matter. The registry record gives the design label but not the analysis model or the details needed to evaluate how these features were addressed. A design term is useful, but it does not substitute for a transparent statistical plan.

The endpoint includes multiple task categories and stimulation conditions, while the record does not reduce it to a single primary contrast. This highlights a common challenge: when there are many plausible comparisons, readers need to know which one was prespecified and how multiplicity was handled. Without that information, it is difficult to distinguish a primary test from exploratory analyses or to interpret uncertainty across several possible results.

Finally, the record separates study completion and enrollment from endpoint-specific evidence. Enrollment of 112 does not reveal how many participants contributed usable data to the primary analysis, and the registry lists no statistical analyses. The safety counts are also group-specific and do not resolve the missing efficacy information. A clear description of what was measured is valuable, but transparent estimates, uncertainty, analysis populations, and missing-data methods are needed to assess what the results mean.

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 endpoint description covers multiple stimulation conditions, task conditions, and time points, but the registry record does not identify a single primary contrast. No mean values, effect estimate, confidence interval, or p-value for the endpoint are reported. This prevents assessment of the direction, magnitude, and precision of any difference.

The record identifies a crossover design but does not report the sequence of conditions for this endpoint, any washout details, or how repeated observations were analyzed. It also does not describe the analysis population, participant flow into the imaging analysis, or the extent and handling of missing measurements. These omissions matter for understanding which observations contributed to comparisons and whether incomplete data could affect interpretation.

The broader intervention and arm descriptions span several populations and study components. The record does not clearly specify which groups contributed to the primary endpoint or how smoking status and nicotine condition were incorporated in its analysis. The study’s background discusses withdrawal and relapse, but the primary endpoint is an imaging measure; the registry record does not provide a primary result for a direct withdrawal or relapse outcome.

The registry lists 11 outcome measures and 0 analyses, and does not report a statistical analysis plan, multiplicity procedure, interim analyses, or sample-size justification. The safety information provides counts for named groups, but does not report event descriptions for the other adverse events or explain how those groups relate to the overall study enrollment. These record-level limitations restrict what can be concluded, independent of the study’s completion status.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Nicotine Withdrawal Symptoms and Smoking Relapse — NCT01511614.
• Registry record last updated 2024-05-31; status last verified 2023-07-25.
• Results first posted 2024-05-31.
• 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

NCT01511614, titled “Nicotine Withdrawal Symptoms and Smoking Relapse,” is listed as a completed, randomized, double-masked crossover study sponsored by the National Institute on Drug Abuse (NIDA). The record gives an enrollment of 112, a start date of 2013-05-20, and a primary completion date of 2020-03-30.

The primary endpoint is mean BOLD percent change in the rACC during a parametric flanker task under tDCS or sham stimulation. The registry describes multiple task and stimulation conditions but does not specify one primary comparison or report its statistical results. It lists 11 outcome measures and 0 analyses.

The record describes a broader study of nicotine withdrawal, brain function, and several treatment or stimulation groups. It reports group-specific adverse-event counts, including 0 serious adverse events and 0 deaths in each listed group. Endpoint-specific analysis populations, missing-data methods, and the statistical plan are not reported in the registry record.