Pharmacokinetic and Subjective Effects of Heated Tobacco Products: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetic and Subjective Effects of Heated Tobacco Products (NCT06356610), a randomized na study. The primary outcome is Baseline-adjusted Plasma Nicotine Concentration Pharmacokinetic (PK) Parameters [Cmax] Assessment.

2. Clinical Question

This is a pharmacokinetic and subjective-effects study, but the primary outcome posted in the registry is the plasma nicotine Cmax assessment. Cmax is the maximum measured concentration over the stated measurement interval. The question is therefore about measured nicotine concentration following product use, not about a clinical health outcome, long-term use, or a treatment effect in a disease population. Subjective effects are mentioned in the study title and description, but secondary results are not posted in the registry record.

3. Trial Design

The registry record describes a randomized, controlled, single-masked, six-way crossover study. Rather than assigning participants to one product group for the whole study, the crossover design schedules product use across a sequence of study sessions. Six randomized sequences specify different orders for Products A through F. This arrangement makes each participant’s product-use periods part of the trial design; it does not, by itself, establish what statistical model was used to analyze those repeated measurements.

Planned enrollment was 80. The study status is completed, with a start date of 2024-02-06 and a primary completion date of 2024-04-14. The registry describes participation as expected to last up to 34 days: a 28-day screening period, including a 5-day at-home heated tobacco product trial period, followed by a 6-day in-clinic confinement period. Product sessions occurred during the in-clinic period, from check-in on Day -1 through the end-of-study visit on Day 6.

The six products comprise four heated tobacco test products and two reference products. The study description identifies the usual-brand combustible cigarette and nicotine gum as the reference products. The outcome entries name Products A through D as test products and Products E and F as reference products, but the record does not identify which of E or F corresponds to each named reference. The product labels should therefore be retained when discussing the posted outcome values.

Single masking is recorded, but the identity of the masked party is not reported in the registry record. The registry identifies randomization and the product sequences, but does not report details of sequence generation or allocation concealment. It also does not report whether the analysis accounted for period, sequence, or possible carryover effects. Those are relevant features to consider in a crossover study, but the record does not establish which were addressed in the analysis.

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: 80 participants enrolled in the Product Trial period and 20 participants were dropped out prior to study randomization on Day -1, resulting in 60 participants randomized into study.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) Population: all participants who used any study product and had both product baseline pre-use and at least one post-use plasma nicotine concentration value.

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: Safety Population: all participants who used any study product. Participants who participated in the product trial only will be included in the Safety Population but summarized separately.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Baseline-adjusted Plasma Nicotine Concentration Pharmacokinetic (PK) Parameters [Cmax] Assessment, measured over from time zero (defined as the start of product use) to 180 minutes post-use on each Day 1 through Day 6.

The primary endpoint is baseline-adjusted plasma nicotine Cmax, reported in ng/mL. Cmax means the maximum measured plasma concentration during the stated observation interval. In this study, that interval begins at time zero, defined as the start of product use, and continues to 180 minutes post-use on each study day from Day 1 through Day 6. Baseline adjustment indicates that the endpoint uses the pre-use plasma nicotine measurement in accounting for concentration values; the registry does not report the specific adjustment formula or analysis model.

Plasma nicotine concentration is used as a pharmacokinetic measure: it describes the concentration of nicotine measured in blood over time after product use. The maximum observed concentration captures one feature of that concentration profile. It does not describe the full profile by itself, and the posted Cmax values do not provide information about all possible pharmacokinetic features such as the timing or duration of concentrations. No other primary endpoint is identified in the record.

The outcome is summarized using geometric means and geometric coefficients of variation. Geometric summaries are useful for concentration measurements that are analyzed on a multiplicative scale, where relative variation may be more meaningful than absolute variation. The geometric coefficient of variation describes dispersion relative to the geometric mean; a larger value indicates more relative variability. The registry provides neither confidence intervals nor direct statistical tests for the product-level Cmax results. Thus, the endpoint is informative as a descriptive measure of peak measured plasma nicotine concentration, while the posted summaries alone do not quantify the uncertainty of differences between products.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the crossover design contribute?

In a crossover study, participants use or receive multiple study conditions in a planned order, so measurements can be collected under more than one condition for the same participant. The registry lists six randomized sequences for the six products. This structure can make within-participant comparisons useful: stable characteristics of a participant are shared across that participant’s product periods. However, the design does not remove the need to account for the timing and order of product use. Period effects, sequence effects, and carryover are general methodological considerations in crossover studies. Whether they were included in this study’s analysis is not reported in the registry record.

The posted results are separate product summaries. They do not provide a within-participant contrast, a model coefficient, or a variance estimate for paired differences. A reader cannot reconstruct those results from the geometric means and geometric coefficients of variation alone. The registry does not report individual-level observations or the statistical model that generated the baseline-adjusted summaries.

Why use geometric summaries?

A geometric mean is a central summary based on multiplicative rather than additive scale. It is often useful for positive measurements such as concentrations when differences are more naturally expressed as relative changes. It should not be interpreted as the arithmetic average. The geometric coefficient of variation summarizes relative dispersion around the geometric mean. It is not a confidence interval, and it does not state how uncertain the estimated mean is.

Because relative variability can be substantial, a central value alone gives an incomplete account of the distribution. In these results the geometric coefficients of variation differ across product labels, and the registry does not provide confidence intervals or distribution plots in the stated details. No claim about the precise shape of the concentration data can be made from the geometric mean and coefficient of variation alone. General statistical interpretation should keep the central tendency and dispersion distinct: one describes a typical level on the chosen scale, while the other describes relative spread.

What does baseline adjustment mean?

Baseline adjustment generally accounts for a measurement taken before the product-use period when estimating or comparing post-use outcomes. That can be useful when pre-use values vary among participants or periods. Here the endpoint is explicitly described as baseline-adjusted, with baseline defined through product baseline pre-use measurements in the population definition. The adjustment method, covariates, and model specification are not reported in the registry record. It is therefore not possible to state whether adjustment used a change score, a model covariate, or another approach.

How should the time window be understood?

The endpoint’s measurement interval starts at time zero, defined as the start of product use, and extends to 180 minutes post-use. Cmax is the maximum measured concentration within that interval. It is an observed maximum among measurements in the specified window, not necessarily a measurement of the true continuous-time maximum. In general, the timing and frequency of blood sampling can affect how well an observed maximum represents the concentration profile. Sampling details beyond the stated interval are not reported in the registry record.

The endpoint timeframe covers each study day from Day 1 through Day 6. This repeated schedule is consistent with the crossover structure, but the registry’s posted results do not explain whether the summaries pool measurements across periods in a particular way, or how missing product-period measurements were handled. Those details matter for interpreting the exact estimand: the quantity a statistical analysis is intended to estimate.

What can the summaries establish?

The geometric means and geometric coefficients of variation support descriptive statements about each product’s reported Cmax distribution. They do not provide the standard error of a paired product difference. A confidence interval for a contrast would describe the range of values reasonably compatible with the data under the specified model and assumptions. No such interval is reported for the primary outcome. Likewise, a p-value would address a particular statistical hypothesis under an analysis plan; no primary-outcome p-value is posted.

General statistical comparisons should account for the design and the dependence among repeated observations. Treating all product measurements as independent would ignore the crossover structure. The record does not report whether the sponsor used an appropriate repeated-measures or crossover model, so no specific analysis method can be attributed to the study. Although the record calls the outcome baseline-adjusted, that label alone is not enough to identify the complete model or its assumptions.

Planning illustrations based on observed effects are not the same as the trial’s original design justification, and are not observed power. The record describes a planning approach using a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a fraction of the observed effect. The actual sample-size illustration values are not included in the stated the registry entries. The trial’s own sample-size justification is not reported in the registry record. In general, sample-size planning depends on the target effect, variability, allocation, and analysis assumptions; a post hoc illustration cannot establish what the original design was powered to detect.

For outcomes with extra-Poisson variation, over-dispersion is a general concern: observed variability can exceed what a simple Poisson model assumes, potentially making standard errors too small if the model is not adapted. This concept does not establish that over-dispersion occurred in this trial. The posted primary endpoint is a concentration measure summarized geometrically, and no count-outcome analysis is reported for it.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure, the baseline-adjusted plasma nicotine Cmax assessment. Four outcome measures are listed overall, but no secondary results are posted in the registry record. The registry lists zero analyses. It does not report a multiplicity adjustment, a hierarchy of hypotheses, or a plan for controlling the family-wise error rate across product comparisons or outcomes. Without posted inferential tests, there is no basis for determining how multiple comparisons were addressed.

Multiplicity arises when several hypotheses are tested, because the chance of at least one false-positive finding can increase as the number of tests grows. In a study involving multiple products, this is a general issue to consider if formal pairwise comparisons are made. The registry does not report which comparisons were prespecified, whether all product contrasts were intended to be tested, or whether any correction was applied. The separate descriptive summaries do not themselves establish that statistical tests were performed.

The outcome population is the pharmacokinetic population: participants who used any study product and had both a product baseline pre-use value and at least one post-use plasma nicotine concentration value. The counts reported for product outcomes are not identical across products. The record does not explain the reasons for missing product-period measurements, state how missing values were handled, or describe sensitivity analyses for missing data. It does not report an intention-to-treat analysis population for this outcome.

In general, missing-data methods depend on why measurements are missing and on assumptions about the relationship between missingness and observed or unobserved outcomes. The registry entries do not identify the missingness mechanism or an imputation procedure. Thus, the posted product summaries describe the participants contributing to each product result, but cannot by themselves show how missing measurements may have affected estimates.

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 events for the overall study product trial group and for each product group. The number affected by serious adverse events is 0 in the overall group of 80 participants and 0 in each product group: 58 for Test Product A, 58 for Test Product B, 60 for Test Product C, 59 for Test Product D, 57 for Reference Product E, and 57 for Reference Product F. Deaths are reported as 0 in every group.

For other adverse events, the registry reports 2 participants affected in the overall study product trial group. The product-specific counts are 1 for Test Product A, 3 for Test Product B, 2 for Test Product C, 1 for Test Product D, 8 for Reference Product E, and 1 for Reference Product F. These are reported counts, not comparative risk estimates. The registry entries do not provide event descriptions, timing, severity classifications for the other adverse events, or statistical comparisons between products.

Zero recorded serious adverse events means none were reported in these groups in the registry record; it does not establish that the chance of such events is zero. Group counts also need to be read in light of the product-specific numbers at risk and the study’s in-clinic duration. The record does not provide additional follow-up information that would support broader conclusions about safety beyond the reported study period.

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

The posted results describe baseline-adjusted maximum plasma nicotine concentrations after use of the six study products. The geometric means and geometric coefficients of variation characterize the recorded endpoint by product label. They offer a descriptive view of typical measured concentration and relative variability during the specified interval, but do not provide a formal comparison between any pair of products.

The registry record does not report confidence intervals, p-values, or comparative effect estimates for the primary outcome. Therefore, the numeric ordering of product-level geometric means should not be interpreted as proof that products differ, nor should similar values be taken as proof that they are equivalent. Precision for a product contrast depends on the variability of within-participant differences and on the analysis model; neither is reported in these results. The product-specific outcome counts also vary, and the record does not explain why.

The crossover design and randomized sequences are important to the intended comparison, but the posted summaries do not show how repeated measurements or product order were modeled. The record does not describe adjustment for period, sequence, or carryover effects. These omissions limit what can be concluded about comparative effects from the summaries alone. The study being completed does not supply missing inferential results.

The endpoint is pharmacokinetic, not a direct measure of subjective response, long-term product use, or clinical health outcome. Although subjective effects appear in the study title and description, secondary outcome results are not posted in the registry record. These Cmax results should therefore be understood within the narrow scope of measured plasma nicotine concentration after product use under the study conditions.

The adverse-event entries show no reported serious adverse events or deaths in the listed groups, alongside the reported counts for other adverse events. They do not establish the absence of risk, and they do not support broad safety comparisons without event details, uncertainty estimates, and adequate follow-up. Overall, the record supports careful description of measured outcomes and safety counts, while leaving comparative uncertainty and several analysis details unreported.

13. Why This Trial Matters Statistically

This study illustrates how a crossover design can be used to examine several products within a common participant group. Randomized sequences distribute product order across participants, while repeated product use makes within-person contrasts a natural analytical consideration. These design features are valuable context for interpreting pharmacokinetic measurements, but the usefulness of the design depends on an analysis that respects the repeated observations and product periods.

The results also show why descriptive summaries and inferential comparisons answer different questions. Geometric means communicate product-specific levels on a multiplicative scale, and geometric coefficients of variation describe relative dispersion. Neither quantity supplies the uncertainty of a paired comparison. A ranking of means alone does not establish a statistically distinguishable effect; comparative estimates and their uncertainty are needed to assess precision.

Another statistical lesson is the importance of defining the analysis population and documenting missing outcomes. The registry gives a pharmacokinetic population definition and product-specific counts, but does not explain the varying counts or the handling of missing measurements. With repeated measures, a participant may contribute to some product summaries but not others, so the population underlying each estimate is relevant to interpretation.

Finally, a completed study record can still lack important statistical reporting. The registry does not post analyses, secondary outcome results, model details, or multiplicity procedures. The absence of those details does not invalidate the descriptive figures, but it limits what can be inferred from them. This is a useful example of the distinction between results that characterize observed measurements and results that estimate or test prespecified product contrasts.

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 interpretation is that the registry posts product-level geometric summaries without comparative effect estimates, confidence intervals, or p-values. The reported Cmax values therefore do not quantify the precision of differences between products. The registry lists zero analyses, and the sponsor’s inferential analysis is not available in the record.

Several features needed to assess the statistical analysis are not reported in the registry record: the model specification, the method of baseline adjustment, how repeated observations were handled, and whether period, sequence, or carryover effects were considered. The sampling schedule within the 180-minute interval is also not reported in the stated details. These details would help determine how the maximum concentration was estimated and how well the analysis reflects the crossover design.

The product-specific outcome counts vary, but reasons for missing measurements and the approach to missing data are not reported. The record defines the pharmacokinetic population but does not report a flow of participants through the product periods or sensitivity analyses. Consequently, the available summaries do not show how incomplete measurements may affect the interpretation.

The registry names the usual-brand combustible cigarette and nicotine gum as reference products, but does not map those types to reference labels E and F in the posted results. Single masking is recorded without identifying who was masked. The record also does not post secondary results for subjective effects. The study description and planned duration provide context, but the reported endpoint and adverse-event counts do not establish long-term effects or outcomes outside the study’s stated measurement period.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetic and Subjective Effects of Heated Tobacco Products — NCT06356610.
• Registry record last updated 2026-03-27; status last verified 2025-11.
• Results first posted 2026-03-27.
• 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

NCT06356610 is a completed randomized, single-masked, six-way crossover study sponsored by Altria Client Services LLC. Planned enrollment was 80. The study enrolled adult menthol and non-menthol combustible cigarette smokers and compared four heated tobacco test products with two reference products across randomized sequences.

The primary outcome was baseline-adjusted plasma nicotine Cmax, measured from the start of product use through 180 minutes post-use on each study day from Day 1 through Day 6. Results are posted as geometric means and geometric coefficients of variation for Products A through F, with product-specific outcome counts. The registry also reports adverse-event counts, including zero serious adverse events and zero deaths in each listed group.

No inferential analyses are posted. Comparative effect estimates, confidence intervals, p-values, secondary outcome results, model details, multiplicity procedures, and missing-data methods are not reported in the registry record. Accordingly, the posted figures support descriptive interpretation of product-level measurements, but do not establish the precision or statistical significance of differences between products.