This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Nicotine's Potential Abuse With Menthol (NCT04535362), a randomized early/phase 1 study. The primary outcome is Drug Effect Questionnaire - Stimulatory Effects.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04535362 |
| Phase | EARLY/Phase 1 |
| Condition | Nicotine Dependence |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Single |
| Enrollment | 16 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Yale University |
| Results posted | Yes |
2. Clinical Question
Population
Smokers with nicotine dependence were studied. The registry lists enrollment of 16 participants and describes the primary-outcome population as participants assessed at any or both points in the crossover design.
Intervention
One arm description says participants would smoke only menthol cigarettes for two weeks. Nicotine is the listed drug intervention.
Comparator
The other arm description says participants would smoke only non-menthol cigarettes for two weeks. The registry identifies the study as randomized and crossover.
Primary question
The study aimed to examine whether switching from menthol to non-menthol cigarettes changes dose-effect curves for positive subjective effects and alleviation of smoking urges as a function of nicotine delivery rate. The listed primary outcome is the Drug Effect Questionnaire stimulatory-effects measure.
In statistical terms, the question concerns whether subjective responses to nicotine differ across the two cigarette-smoking conditions. A crossover design can make comparisons within the same participant, but the registry record does not report the specific analysis used to account for that structure. It also does not report numerical primary-outcome results, an estimated difference between conditions, or a confidence interval. Accordingly, the registry record describes the research question and measurement approach, but does not establish the direction or precision of a condition difference.
3. Trial Design
The registry identifies NCT04535362 as an early phase 1, randomized, single-masked, crossover study sponsored by Yale University. Its status is completed. The registry lists a start date of 2021-06-28 and a primary completion date of 2023-06-29, with enrollment of 16. The listed condition is nicotine dependence.
The arm descriptions specify two weeks of smoking only menthol cigarettes in one condition and two weeks of smoking only non-menthol cigarettes in the other. The listed intervention is nicotine. The study summary frames the aim as examining whether switching from menthol to non-menthol cigarettes changes dose-effect curves for positive subjective effects and alleviation of smoking urges according to nicotine delivery rate.
In general, a crossover design exposes participants to more than one condition and can support within-participant comparisons. Such designs require attention to the sequence of conditions, changes over time, and whether effects from an earlier condition could persist into a later one. The registry record does not report the condition sequence, the method of randomization, a washout period, or how period and carryover effects were handled. It also does not identify who was masked or describe the masking procedure. Those details therefore cannot be inferred from the design labels alone.
The primary outcome assessment is described as occurring following two weeks of smoking. The procedure took over 3 hours, with measured effects at 2.5 minutes, 5 minutes, and 10 minutes. The registry lists SAFTEE as a secondary outcome and reports five outcome measures and four analyses. It does not explain how those analyses map to outcomes or measurement occasions.
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
| Stage | Menthol FIRST, Non-Menthol SECOND | Non-Menthol FIRST, Menthol SECOND |
|---|---|---|
| STARTED | 8 | 8 |
| Entered Phase 1 | 8 | 8 |
| Completed Phase 1 | 8 | 8 |
| Entered Phase 2 | 8 | 8 |
| Completed Phase 2 | 5 | 7 |
| COMPLETED | 5 | 7 |
| NOT COMPLETED | 3 | 1 |
Reasons for not completing this period:
| Reason | Menthol FIRST, Non-Menthol SECOND | Non-Menthol FIRST, Menthol SECOND |
|---|---|---|
| Lost to Follow-up | 3 | 1 |
Analysis population for the primary outcome, as defined in the registry: Participants assessed an any or both points in the crossover design.
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 randomized to one of two crossover arms.
| Characteristic | Unit | Study Participants |
|---|---|---|
| Participants analysed | 16 | |
| Age, Continuous | years | 32.4 (SD 4.5) |
| Sex: Female, Male: Female | Participants | 5 |
| Sex: Female, Male: Male | Participants | 11 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 12 |
| Race (NIH/OMB): White | Participants | 3 |
| Race (NIH/OMB): More than one race | Participants | 1 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Region of Enrollment: United States | participants | 16 |
| Average number of cigarettes consumed daily | cigarettes per day | 10.5 (SD 4.7) |
| Fagerstrom Test for Nicotine Dependence (FTND) | units on a scale | 4.2 (SD 2.4) |
6. Primary Endpoint
The registry lists the primary outcome as Drug Effect Questionnaire - Stimulatory Effects, measured over Following 2 weeks of smoking, the procedure took over 3 hours, with measured effects at 2.5 minutes, 5 minutes and 10 minutes.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | units on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is titled Drug Effect Questionnaire - Stimulatory Effects. The registry says participants completed the Drug Effects Questionnaire, described as ten items rated on a visual analog scale from 1 to 100, ranging from “not at all” to “extremely.” The stimulatory-effects score is described as the average of the items “feel stimulated,” “feel drug effects,” and “feel high.” The record says subscale scores range from 0 to 100, with 0 representing the least impactful effect.
This endpoint is intended to quantify participants’ subjective experience of stimulation and related drug effects. In general, a continuous rating can preserve gradations in reported experience rather than reducing responses to a yes-or-no category. Averaging related items can provide a domain score, but interpretation depends on how the items are combined and how that score behaves in the study population. The registry gives the item content and scoring description, but does not report reliability or other measurement-performance results.
The assessment is described in relation to a procedure lasting over 3 hours, with effects measured at 2.5 minutes, 5 minutes, and 10 minutes. The primary outcome has several categories or time points and is not reduced in the registry record to one comparison. No condition-specific means, standard deviations, effect estimate, or uncertainty interval for this endpoint are reported in the registry record. Thus, the endpoint definition is available, but the size and precision of any difference are not.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record defines a randomized crossover question about subjective responses under menthol and non-menthol cigarette-smoking conditions. It does not report numerical results for the primary Drug Effect Questionnaire stimulatory-effects outcome. Without those results, the direction, magnitude, and precision of a difference between conditions cannot be described. No conclusion about whether responses changed is supported by the outcome information recorded.
The primary measure is continuous and is described as a mean, with standard deviation as its dispersion measure. In general, a mean describes the average score in a group or condition, while a standard deviation describes how spread out individual scores are around that average. A difference between condition means could be informative, but its interpretation would depend on the estimate, its uncertainty, and the crossover analysis. None of those numerical primary-outcome results is reported in the registry record.
The registry describes assessments at 2.5 minutes, 5 minutes, and 10 minutes, and the listed primary outcome is not reduced to a single comparison. Responses at those measurement occasions may represent different parts of the assessment procedure. A reader would need the prespecified contrast and analysis approach to know whether the scientific target was a condition difference at a particular time, a pattern across measurement occasions, or another summary. The registry record does not report that target or the corresponding estimates.
In general, a confidence interval expresses the range of values compatible with an estimate under the assumptions of the statistical model. A narrow interval indicates greater precision than a wide interval, while an interval crossing a null value may still include effects that matter scientifically. No confidence interval is reported for the primary outcome, so precision cannot be evaluated from the registry entry. A p-value is also not reported for this comparison. Neither statistical significance nor practical importance can be judged from the endpoint description alone.
The record reports zero serious adverse events and zero other adverse events in the stated at-risk groups, alongside zero deaths. Those are the posted safety counts, not estimates of the primary subjective-effect difference. The safety denominators differ by condition, and the record does not explain the reason. The figures should be read as registry-reported counts rather than as proof that no adverse effects could occur.
Overall, the record supplies design and measurement information but not the primary effect estimate. The trial status of completed does not itself reveal the outcome. A complete statistical interpretation would require condition-specific results, the analysis population, the handling of repeated measurements and crossover structure, and the uncertainty around the planned comparison; those details are not reported in the registry record.
9. Statistical Methods Explained
The registry classifies the primary outcome as a continuous measure summarized by a mean and standard deviation. It names the Drug Effect Questionnaire stimulatory-effects score and describes assessments at multiple time points. The numerical outcome summaries and the method used to compare conditions are not reported in the registry record.
What does a mean describe?
In general, a mean is the arithmetic average of the observed scores included in an analysis. It gives a compact description of the location of a distribution, but it does not show the full pattern of individual responses. Participants may have similar scores or widely varying scores while sharing the same mean. A mean should therefore be read alongside a measure of spread and the definition of the analysis population.
The registry names standard deviation as the dispersion measure. In general, standard deviation describes the spread of observations around the mean, using the same measurement scale as the score. It is not a measure of uncertainty in the mean itself. The uncertainty of an estimated condition difference is usually conveyed through an interval estimate or another inferential measure; those primary-outcome statistics are not reported in the registry record.
Why does the crossover structure matter?
In general, a crossover comparison can use observations from the same participant under different conditions. This can account for stable differences between participants, because each participant may contribute information to more than one condition. That benefit depends on suitable design and analysis assumptions. The analysis needs to respect the repeated observations and the order in which conditions were received. The registry record identifies the design as crossover but does not report the statistical model, the randomization sequence, or how period and carryover effects were assessed.
A simple comparison of unrelated group means would not necessarily capture the structure of a crossover study. In general, paired or repeated-measures methods account for the relationship between observations from the same participant. The registry record does not say whether such a method was used, nor does it report a recalculated comparison from posted summary statistics. The analysis method and any sponsor-reported estimate therefore cannot be reconstructed from the available outcome details.
How should multiple measurements be understood?
The primary outcome description includes assessments at 2.5 minutes, 5 minutes, and 10 minutes. In general, repeated measurement occasions can be handled as separate comparisons, as a combined response pattern, or through a model that represents change over time. Those choices answer different questions. Selecting among them can affect the estimated condition effect and its uncertainty. The registry record says the primary outcome has several categories or time points and is not reduced to one comparison, so no single contrast should be assumed.
When an analysis includes repeated observations, the observations may be correlated rather than independent. In general, accounting for that correlation helps estimate uncertainty appropriately. The exact correlation structure, model, and treatment of incomplete repeated measurements are not reported in the registry record. It is therefore not possible to assess whether the analysis used all available observations or how it addressed dependence between them.
What do uncertainty and significance measures add?
In general, an effect estimate describes the size and direction of a comparison, while a confidence interval communicates uncertainty around that estimate. A p-value addresses compatibility of the data with a specified null hypothesis under the model; it is not a measure of effect size or clinical importance. These statistics must be interpreted in the context of the prespecified comparison, the analysis assumptions, and the measurement scale. The registry record does not report a primary-outcome effect estimate, confidence interval, or p-value.
The registry includes no protocol-level statistical plan in the registry record recorded for this analysis. The planned contrast, covariate adjustment, assumptions, and handling of repeated measures are not reported in the registry record. No interim analysis plan is reported. These absences mean that the analysis cannot be evaluated against a documented plan from the registry entry alone; they do not establish what may have been specified elsewhere.
What do planning calculations mean?
In general, sample-size planning asks how many participants per arm would be needed to detect a chosen effect under stated assumptions. The registry’s planning description refers to a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. It also says that time-to-event calculations use total events, while other calculations use participants per arm. These are planning assumptions, not evidence of the trial’s observed power.
A sample-size illustration based on an observed effect does not show that the trial had a particular probability of detecting an effect after the results are known. In general, post hoc observed-power calculations add little beyond the effect estimate and its uncertainty. No planning sample-size values are reported in the registry record for interpretation here, and the record does not report the trial’s own sample-size justification. The planning assumptions cannot substitute for the missing primary-outcome estimate.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists five outcome measures and four analyses. It names the Drug Effect Questionnaire stimulatory-effects measure as primary and SAFTEE as a secondary outcome. The primary outcome description includes several questionnaire domains and measurement occasions, and the registry explicitly notes that this outcome has several categories or time points and is not reduced to one comparison.
Multiplicity arises in general when several outcomes, contrasts, or time points are tested. If each is examined separately, the chance of at least one apparently unusual result can increase. A study may address this through a prespecified hierarchy, adjustment, or a clearly defined primary contrast. The registry record does not report a multiplicity strategy, identify which comparisons were confirmatory, or map the four analyses to the five outcome measures. It is therefore not possible to determine how multiple comparisons were handled.
The record does not report a missing-data method, the number of participants contributing to each primary-outcome analysis, or the reasons for any unavailable outcome observations. The primary-outcome population is described as participants assessed at any or both points in the crossover design, but the meaning of that wording for analysis inclusion is not clarified. The registry also does not report whether all randomized participants were analyzed or how incomplete crossover participation was treated.
In general, missing observations can affect both the estimate and its precision, particularly when their availability is related to participants’ responses or condition exposure. The extent and direction of any such effect cannot be assessed without counts, reasons, and an analysis description. The analysis populations and missing-data handling are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Menthol | 0 | 16 | 0.0% |
| Non-Menthol | 0 | 13 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Menthol | 0 of 16 |
| Non-Menthol | 0 of 13 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Menthol | 0 of 16 |
| Non-Menthol | 0 of 13 |
The registry reports zero serious adverse events among 16 at risk in the Menthol group and zero among 13 at risk in the Non-Menthol group. It also reports zero other adverse events in those respective at-risk groups and zero deaths in each group. No serious adverse-event terms are listed.
These figures are counts recorded for the stated groups. In general, zero recorded events means no events of that category were reported in the registry for the listed at-risk group; it does not establish that the risk is absent. The counts alone also do not provide a precise estimate of event frequency or enable a meaningful comparison of safety between conditions.
The at-risk counts differ between the two conditions, while the trial is described as crossover and enrollment is listed as 16. The registry record does not explain the difference in at-risk counts. It should not be interpreted as evidence of a particular reason for missing exposure, withdrawal, or analysis exclusion. The adverse-event figures are separate from the subjective primary endpoint and do not provide information about its effect estimate.
12. What the Result Does, and Does Not, Mean
The registry record establishes that NCT04535362 was a completed, randomized, single-masked crossover study of menthol and non-menthol cigarette-smoking conditions in smokers with nicotine dependence. Its stated aim was to examine whether switching conditions changes dose-effect curves for positive subjective effects and alleviation of smoking urges in relation to nicotine delivery rate. The primary measure is a Drug Effect Questionnaire stimulatory-effects score.
What the record does not establish is the numerical outcome of that question. It does not report condition-specific means or standard deviations, a contrast between conditions, an uncertainty interval, or a p-value for the primary endpoint. Without those quantities, it is not possible to say whether the posted data indicate higher or lower scores in either condition, how large a difference may be, or how precisely it is estimated.
In general, a statistically detectable difference and a meaningful difference are not the same thing. Interpretation depends on the size of the estimate, its uncertainty, the scale’s measurement properties, and the scientific context. The registry entry does not provide the results needed to make that assessment. The study’s completed status, its design labels, and the endpoint definition are not substitutes for outcome results.
The zero adverse-event counts are limited to the categories and at-risk groups recorded in the registry. They do not establish that a condition has no safety risk, and they do not answer the primary subjective-effect question. The unequal at-risk counts are not explained in the registry record.
The sound conclusion is therefore bounded: the record describes a trial intended to compare subjective effects across smoking conditions, but it does not report the primary comparison needed to characterize the observed result. Any account of the direction, size, statistical significance, or clinical importance of that result would go beyond what is reported in the registry record.
13. Why This Trial Matters Statistically
This trial is statistically notable because its crossover design and repeated subjective ratings create an analysis question more specific than a simple comparison of independent groups. Participants may contribute measurements under more than one condition, and the assessment includes multiple time points. In general, the analysis must align with that structure to estimate a condition contrast and its uncertainty appropriately.
The endpoint also combines questionnaire items into a domain score. That makes the interpretation depend on both the individual ratings and the scoring rule. The registry describes the items used for stimulatory effects and the score range, but does not report measurement-performance findings or the numerical outcome summaries. Readers can understand what was intended to be measured without being able to evaluate the observed contrast.
The record illustrates why a completed-trial label is distinct from a reported statistical result. Design, endpoint definitions, and safety counts convey useful information, but do not supply an effect estimate. Clear reporting of the prespecified contrast, condition-level summaries, uncertainty, analysis population, and handling of repeated measurements would be necessary to assess the primary question.
It also matters that multiple outcome measures and analyses are listed while the primary outcome spans categories or time points. Without a reported multiplicity approach and a clear mapping between analyses and outcomes, the inferential role of each comparison is uncertain. The registry record thus makes the structure of the research question visible while leaving important elements of its statistical answer unreported.
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 most consequential limitation of the registry record for interpreting this trial is that numerical results for the primary endpoint are not reported. There is no condition-specific mean or standard deviation, no primary contrast, and no uncertainty estimate. Consequently, the result’s direction, size, and precision cannot be evaluated.
The primary outcome includes several categories or time points, but the registry does not identify a single contrast or explain how those measurements were combined or compared. The statistical method for the crossover structure is also not reported. Randomization sequence, condition order, washout information, and handling of period or carryover effects are absent from the registry record. These details matter for understanding how within-participant observations were interpreted.
The analysis population is not fully specified. The outcome description refers to participants assessed at any or both points in the crossover design, but does not clarify inclusion rules or report outcome-specific participant counts. The registry also does not describe missing-data handling, the reasons for unavailable observations, or whether all randomized participants were included in each analysis.
Multiplicity is another limitation: five outcome measures and four analyses are listed, but the record does not map analyses to outcomes or report an adjustment or hierarchy. The record also does not identify who was masked or explain the masking procedure. These limitations concern what can be learned from the registry record and should not be taken as evidence about what was or was not documented elsewhere.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Nicotine's Potential Abuse With Menthol — NCT04535362.
- Registry record last updated 2024-08-26; status last verified 2024-08.
- Results first posted 2024-08-26.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT04535362, titled “Nicotine’s Potential Abuse With Menthol,” is listed as an early phase 1, randomized, single-masked crossover study sponsored by Yale University. The registry reports that it is completed, with enrollment of 16, a start date of 2021-06-28, and a primary completion date of 2023-06-29. The listed condition is nicotine dependence.
The arm descriptions specify two weeks of menthol-cigarette smoking or two weeks of non-menthol-cigarette smoking. The primary outcome is the Drug Effect Questionnaire stimulatory-effects score, assessed following two weeks of smoking with measurements at 2.5 minutes, 5 minutes, and 10 minutes during a procedure lasting over 3 hours. SAFTEE is listed as a secondary outcome.
The registry record does not report numerical results for the primary outcome or the analysis details needed to interpret a condition contrast. It records zero serious adverse events, zero other adverse events, and zero deaths in the stated at-risk groups.