A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of Heated Tobacco Products Compared to Combustible Cigarettes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of Heated Tobacco Products Compared to Combustible Cigarettes (NCT05459857), a randomized na study. The primary outcome is Nicotine Cmax.

2. Clinical Question

The registry describes a pharmacokinetic and pharmacodynamic study, with nicotine concentration as its primary outcome and subjective smoking-urge measures as secondary outcomes. The clinical question is therefore about measured nicotine exposure and reported urges during the study sessions. It is not a question about long-term health outcomes, sustained product use, or whether one product should be chosen for an individual.

Products A through D were assigned in four sequences. Each sequence includes all four products, but the order differs. This design allows participants to experience more than one product. The registry record does not report how period effects, sequence effects, or within-participant correlation were handled in an inferential analysis. The posted comparison estimates therefore need to be read as unadjusted comparisons derived from product-level summary statistics, not as a fully documented cross-over model.

3. Trial Design

This was a randomized, open-label, cross-over study with an enrollment of 24. Its status is completed. The registry dates the study start as 2021-10-01 and primary completion as 2021-11-30. The study is listed as phase NA. It was sponsored by Imperial Brands PLC.

Participants were adult male or female smokers of combustible cigarettes, and the condition is listed as healthy volunteers. The brief description says participants completed a screening visit and a 5-day confinement period. The four products were used on four consecutive study days within the sequences described in the registry: ABCD, BDAC, CADB and DCBA. The sequence descriptions specify which letter was used on each day, but do not explain how participants were allocated among sequences or give sequence-specific participant counts.

Randomization is listed as the allocation method, and masking is listed as none. The four intervention labels are all classified as other. Although the study title describes heated tobacco products compared with combustible cigarettes, the registry's intervention and sequence descriptions do not map Products A–D to those categories. That product-level identification is not reported in the registry record.

The crossover structure means that a participant may contribute measurements under more than one product, unlike a parallel study in which each participant receives only one assigned product. This matters statistically because observations from the same participant can be related. The registry record does not report whether the comparisons accounted for that dependence, nor does it describe washout procedures, period effects, carryover assessment, or a model for the crossover data. These details should not be inferred from the sequence names alone.

The primary outcome population includes participants who used a specific product. The reported counts differ by product: Product A and Product D have 23 participants each, while Product B and Product C have 24 each. The registry explicitly notes that product-level analysis counts can differ from arm counts in the participant-flow module. Detailed participant flow by sequence and reasons for any missing product-specific 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

Analysis population for the primary outcome, as defined in the registry: The analysis population represents all subjects who used a specific product. The overall number of participants analyzed for each product is therefore different from the number of participants in each arm provided in the Participant Flow module.

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 Nicotine Cmax, measured over 5 minutes pre-study product use and at 2, 4, 6, 8, 10, 15, 30, 45, 60, 120, and 240 minutes following the start of study product use.

The primary endpoint is Nicotine Cmax: the maximum measured plasma nicotine concentration, adjusted for baseline. It is reported as a mean in ng/mL, together with a standard deviation. Concentrations were scheduled at 5 minutes before study product use and at 2, 4, 6, 8, 10, 15, 30, 45, 60, 120 and 240 minutes after use began.

In general, a maximum concentration summarizes the highest measured value in a sampling window. It is used in pharmacokinetic assessment because it describes the peak concentration observed after exposure, rather than the concentration at one selected time alone. Baseline adjustment is intended to account for the pre-use level when describing the post-use measure. This endpoint is a measure of nicotine concentration over the specified observation period; it does not by itself describe the full concentration-time profile or longer-term outcomes.

The registry reports the endpoint as a product-level mean and standard deviation, not as a model-based estimate with a stated adjustment for sequence, period, or participant. The record does not state the exact baseline-adjustment calculation or identify the statistical model used for the primary endpoint. Those analysis details are not reported in the registry record, so the posted summaries do not establish how within-person measurements were incorporated into an original sponsor analysis.

Nicotine Cmax is a pharmacokinetic outcome. It should be distinguished from the secondary subjective measures of urge to smoke. These outcomes capture different aspects of the study: concentration measurements characterize nicotine exposure, while urge scores are questionnaire-based measures. Neither type of measure alone establishes longer-term effects or answers questions beyond the outcomes and observation period recorded for this trial.

7. Results Posted in the Registry

• Product B: mean 7.54 versus 10.50 on control; difference -2.96 (95% CI -6.82 to 0.90), standardized effect d = -0.44; z-test p = 0.133.
• Product C: mean 8.19 versus 10.50 on control; difference -2.31 (95% CI -6.13 to 1.52), standardized effect d = -0.35; z-test p = 0.237.
• Product D: mean 21.68 versus 10.50 on control; difference 11.18 (95% CI 5.61 to 16.75), standardized effect d = 1.16; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Urge to Smoke Pre-Use

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Product B: mean 57.80 versus 63.80 on control; difference -6.00 (95% CI -22.88 to 10.88), standardized effect d = -0.21; z-test p = 0.486.
  • Product C: mean 64.20 versus 63.80 on control; difference 0.40 (95% CI -15.90 to 16.70), standardized effect d = 0.01; z-test p = 0.962.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Product B and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Product C and the control. The interval gives the range of effects that remain compatible with the data.

Urge to Smoke Post-Use

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Product B: mean 67.50 versus 61.40 on control; difference 6.10 (95% CI -9.39 to 21.59), standardized effect d = 0.22; z-test p = 0.440.
  • Product C: mean 71.30 versus 61.40 on control; difference 9.90 (95% CI -4.40 to 24.20), standardized effect d = 0.39; z-test p = 0.175.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Product B and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Product C and the control. The interval gives the range of effects that remain compatible with the data.

Smoking Urges Emax

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Product B: mean 32.90 versus 40.30 on control; difference -7.40 (95% CI -22.69 to 7.89), standardized effect d = -0.28; z-test p = 0.343.
  • Product C: mean 39.70 versus 40.30 on control; difference -0.60 (95% CI -16.48 to 15.28), standardized effect d = -0.02; z-test p = 0.941.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Product B and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Product C and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover urge to smoke before product use, urge to smoke at 240 minutes after use began, and Smoking Urges Emax across specified measurement times. Together, they provide subjective measures at different points in the session, distinct from the primary pharmacokinetic measure of nicotine concentration. The registry reports product-level means and standard deviations for these outcomes, with some variation in the number analyzed across product and measure.

Across the secondary measures, the posted summaries do not show one uniform direction of difference between Product A and each other product. The recalculated comparisons are unadjusted, and their intervals generally leave room for a range of possible differences. This broad pattern does not establish a consistent relation between the nicotine concentration result and participants' urge scores. The endpoints measure different constructs, and the registry record does not report a prespecified analysis linking them or a model for their joint interpretation.

Secondary results carry less weight than a prespecified primary result for several reasons. In general, testing multiple outcomes and multiple product comparisons creates more opportunities for apparently notable findings to arise by chance. A multiplicity adjustment or a stated hierarchy can address some of that issue, but the registry record does not report such a procedure. The posted secondary comparisons should therefore be regarded as exploratory descriptions rather than independent confirmation of the primary result.

The record identifies three secondary outcome names, but the number of outcome measures is listed as five. It also lists no reported analyses for the secondary outcomes. The available summaries are enough to describe group means and recalculated comparisons, but they do not establish which secondary contrasts were prespecified, how missing observations were handled, or whether any measures were selected for emphasis after results were known. Those analysis details are not reported in the registry record.

The secondary outcomes can add context about the types of measurements collected, but they do not replace the primary endpoint or answer longer-term questions. Because the scale's scoring details and clinically meaningful thresholds are not reported, the size of a score difference cannot be assigned a practical interpretation from the posted record alone.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Urge to Smoke Pre-Use
• Urge to Smoke Post-Use
• Smoking Urges Emax

9. Statistical Interpretation

10. Statistical Methods Explained

For a continuous measure, a mean describes the average observed value in an analysis group. A standard deviation describes how spread out individual observations are around that mean. These two summaries answer different questions: the mean locates the group average, while the standard deviation conveys variation among participants. A mean should not be interpreted as the value experienced by every participant, and a standard deviation is not a confidence interval for the mean.

What the primary comparison represents

The posted primary comparisons use Product A as the reference and give a mean difference for each of Products B, C and D. A difference below zero means the product mean in the comparison is lower than the reference mean; a difference above zero means it is higher. The comparison estimates are simple unadjusted recalculations from posted product-level means and standard deviations. The registry record does not report a corresponding sponsor inferential analysis, its model, or its treatment of the repeated observations within participants.

That distinction matters in a cross-over study. In general, measurements from the same participant are often correlated, because people can differ consistently in their baseline levels or responses. A paired or repeated-measures analysis can use this within-person structure. A calculation based only on separate product-level summaries does not reveal the within-participant covariance and cannot reconstruct a participant-level paired analysis. The recalculated estimates therefore should be understood as unadjusted summaries, not as proof that the trial's original analysis treated the data as independent groups.

How to interpret the interval and p-value

In general, a confidence interval gives a range of values compatible with the estimate under the statistical procedure used. Its width reflects precision: a wider interval indicates more uncertainty about the difference. An interval that includes zero does not establish that the groups are equivalent; it means that the data and the specified calculation do not distinguish the estimated effect from no difference at the selected confidence level.

A p-value describes how unusual data at least as incompatible with a null hypothesis would be if that hypothesis and the analysis assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of an effect. The posted unadjusted p-values do not account for multiple comparisons unless an adjustment is explicitly applied; no such adjustment is reported in the registry record. The conventional threshold is not reported as part of the registry's analysis plan.

Why crossover details matter

General statistical reasoning for crossover trials recognizes that the observed outcome may depend not only on the product used but also on the period and order in which it was used. Carryover from an earlier product and changes over successive study days can also be relevant design considerations. The registry gives four use sequences but does not report whether these effects were evaluated, whether a washout was used, or how any such effects entered an analysis. It would be inappropriate to infer the answer from the sequence schedule.

The registry reports means and standard deviations for each product and defines the primary analysis population by product use. These summaries do not provide the cross-tabulation of each participant's values across products. As a result, the observed product means can be described, but the precision of a properly paired contrast cannot be determined from the posted summaries alone. The confidence intervals and p-values discussed for contrasts are recalculations from the summary statistics and should be distinguished from a documented model-based crossover analysis.

Variation and outcome measurement

General statistical interpretation treats variation as important context for a mean difference. When observations vary widely, a group mean may be estimated less precisely for a given number of participants. Nicotine Cmax has appreciable standard deviations across products, and the outcome is the maximum among scheduled concentration measurements. The recorded maximum can depend on the sampling schedule, so it describes the peak measured under the stated schedule rather than an unobserved continuous-time maximum.

The secondary outcomes are questionnaire-based urge measures summarized as means and standard deviations. Their units are described as units on a scale, but the scale's range, scoring method, and interpretation are not reported in the registry record. Thus, the numerical results describe the posted score summaries; they do not by themselves establish what size of score change would be important to participants.

Overall, the statistical evidence available in the registry is limited to descriptive summaries and recalculated unadjusted comparisons. The registry record does not report the original sample-size justification, prespecified analysis methods, missing-data method, interim analyses, or a multiplicity procedure. These absences limit conclusions about whether the posted calculations match the planned primary analysis and how the study intended to handle all outcomes and comparisons.

11. Confidence Intervals and Precision

Precision is best assessed from the confidence intervals alongside the point estimates, not from the point estimates alone. For Product B compared with Product A, the unadjusted mean difference is -2.961 ng/mL and the 95% confidence interval runs from -6.825 to 0.903. For Product C compared with Product A, the estimate is -2.309 ng/mL and the interval runs from -6.134 to 1.516. Both intervals include zero and allow a range of possible differences on either side of zero.

For Product D compared with Product A, the unadjusted estimated mean difference is 11.18 ng/mL, with a 95% confidence interval from 5.614 to 16.75. This interval does not include zero under the recalculation. It still expresses uncertainty about the size of the difference: the estimate is not known without error, and the interval is not a statement that every participant had a difference within those limits.

In general, a confidence interval reflects the data and assumptions of the calculation used to produce it. Here, the comparisons are unadjusted recalculations from posted summaries. The registry record does not report confidence intervals from a crossover model accounting for within-participant dependence, sequence, or period. Therefore, the displayed precision does not resolve the uncertainty about how a prespecified, participant-level analysis would have estimated these contrasts.

The product-specific analysis counts are 23 for Product A, 24 for Product B, 24 for Product C and 23 for Product D. These counts are close but not identical, and the standard deviations indicate variation among observations. The registry notes that analysis counts represent participants who used each product and can differ from participant-flow arm counts. Reasons for the product-specific differences are not reported in the registry record. The interval widths should be read as uncertainty under the unadjusted calculation, not as a complete account of uncertainty from the trial design and analysis process.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on observed effects, not the trial's original design assumptions. For these continuous outcomes, the displayed values are participants per arm, rather than total event counts. The planning calculation assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers detecting the full observed effect, 75% of the observed effect, or 50% of the observed effect. The trial's own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% probability of detecting the specified effect if that effect were the true one and the planning assumptions held. The 90% power column gives the corresponding planning count for a 90% probability under those same assumptions. These are design probabilities in a hypothetical study, not probabilities that the observed results are correct or that a treatment effect exists.

The display makes the effect-size dependence visible: planning for a smaller fraction of the observed effect requires more participants than planning for the full observed effect. Very small observed differences can produce very large illustrative sample-size figures. This reflects the difficulty of distinguishing a small difference from random variation under the stated assumptions; it is not evidence that such a study was conducted or planned.

These figures are not observed power. They are not a retrospective measure of whether this completed trial was adequately powered, and they do not account for unreported crossover features such as paired correlation or sequence effects. The registry record does not report the study's original sample-size calculation, so the illustrations should be read only as conditional planning scenarios based on the posted summaries and stated assumptions.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -2.961; pooled standard deviation σ = 6.679.
2. n = 2 × (1.96 + 0.842)² × 6.679² / -2.961² = 79.9, rounded up to 80 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -2.961                      # observed difference in means
sigma <- 6.67949073075352                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(5459857)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 80 (80% power), 107 (90% power)
 75% of observed effect: n per arm = 143 (80% power), 191 (90% power)
 50% of observed effect: n per arm = 320 (80% power), 428 (90% power)
power.t.test: 80.9 
Simulated power at n = 80 per arm: 0.799 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The study includes a primary outcome, several secondary outcomes, and multiple product comparisons. In general, testing many hypotheses increases the chance that at least one result appears unusual even when there is no underlying difference. Statistical methods may control this issue through adjustment, a prespecified testing order, or another planned strategy. A multiplicity strategy is not reported in the registry record. The unadjusted recalculated comparisons should therefore not be read as though they were corrected for the full set of outcomes and contrasts.

The registry record also does not report a statistical analysis plan, the model used for the primary outcome, or any interim analyses. It does not describe whether analyses were adjusted for sequence, period, baseline, or participant-level repeated measurements beyond the endpoint's description as baseline-adjusted. The reported primary endpoint definition does not provide enough detail to reconstruct the model or its assumptions.

Missing-data handling is not reported in the registry record. Product-specific outcome counts vary, and the primary analysis population is described as participants who used a specific product. That definition clarifies why counts can differ, but it does not explain why any participant lacks a value for a product or how missing values were treated. The record does not report whether missingness was assessed, whether imputation was used, or whether sensitivity analyses were conducted.

The four treatment sequences are listed, but participant numbers by sequence and the handling of order-related effects are not reported. For a cross-over design, these details matter because each participant may contribute outcomes under several products and measurements can be related within a person. The posted product summaries do not provide enough information to assess that dependence or reconstruct a paired analysis.

These gaps do not invalidate the descriptive results, but they constrain inferential interpretation. The recalculated comparisons are useful as transparent summaries of the posted means and standard deviations. They cannot supply missing information about prespecification, multiplicity control, missing-data assumptions, or the planned crossover model.

15. 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 zero serious adverse events considered related to study products for each product group. It also reports zero deaths in every product group. The numbers at risk for serious events are 24 for Product A, Product B and Product C, and 23 for Product D. These counts describe the safety information posted for the study; they do not establish that no serious event of any kind occurred, only that none was recorded as a serious event related to the product in these group summaries.

The registry lists other adverse events considered related for Product A, Product B and Product C, and none for Product D. These are separate from the serious-event counts. The safety record does not provide event terms for serious events, and the listed serious-event terms are empty. The record's safety summaries are based on the stated product-specific numbers at risk, which can differ because of the crossover exposure pattern.

In general, a small study and a short observation period can provide only limited information about uncommon or delayed events. This study involved a 5-day confinement period, and the safety figures should be interpreted within that study setting and timeframe. They are not a comprehensive estimate of longer-term safety or a comparison of risks outside the participants and exposure observed in this trial.

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

The results describe short-term measurements collected during a confined cross-over study in adult smokers. The primary endpoint is a baseline-adjusted maximum plasma nicotine concentration observed during scheduled sampling through 240 minutes after product use began. The posted product-level means differ, and the unadjusted recalculated comparisons suggest a higher mean for Product D than Product A, while the Product B and Product C estimates are lower than Product A with confidence intervals that include zero.

These findings do not identify which of Products A–D corresponds to heated tobacco or combustible cigarettes. The title describes a comparison of those product categories, but the registry's intervention labels and sequence descriptions do not specify the mapping. It is therefore not possible to attribute the product-level estimates to a particular product category using the posted record alone.

The comparison estimates are not a documented sponsor analysis. They are simple unadjusted recalculations from posted means and standard deviations. The registry record does not report whether an analysis accounted for repeated measurements within a participant, period, sequence, or possible carryover. A reader should not treat the recalculated p-values as a complete analysis of a crossover trial.

Nor do the results establish long-term effects, outcomes beyond the measured endpoints, or what an individual participant would experience. Nicotine Cmax is a measured pharmacokinetic outcome; urge-to-smoke scores are subjective scale outcomes. The registry does not report the scale range or a threshold for a meaningful change. These measures do not answer questions about longer-term health or product use.

The safety summaries report no product-related serious adverse events and no deaths, while also recording some other product-related adverse events in three product groups. The counts are limited to this study's participants, products, exposure schedule, and observation period. They should not be generalized to uncommon events or longer-term risks.

The most defensible interpretation is descriptive: the posted summaries show differences in measured nicotine concentrations among product labels, with uncertainty that varies across contrasts. The strength and scope of conclusions are constrained by the small study enrollment, unavailable product mapping, and absent details of the planned statistical analysis.

17. Why This Trial Matters Statistically

This trial is statistically notable because it uses a cross-over structure to collect measurements for four products from participants during a confined study period. Such designs can make within-person comparisons possible, but they also require analysis methods that account for the relationship between measurements from the same person and the order in which products are used. The registry lists the product sequences, yet does not report the analysis model or how order-related features were handled.

The record also illustrates the distinction between descriptive summaries and an inferential analysis. Product means and standard deviations convey the observed levels and variation, while recalculated mean differences and confidence intervals add an unadjusted comparison. Without a reported sponsor model, however, those calculations do not reveal whether the original analysis used the crossover information efficiently or addressed the design's structure.

Another important statistical issue is multiplicity. There are several outcomes and comparisons, but the registry does not report a multiplicity procedure or testing hierarchy. This makes it important to distinguish the primary endpoint from secondary measures and to avoid treating each unadjusted result as an independent confirmatory finding.

The study's posted sample-size illustrations also help clarify the relationship between effect size, precision, and planning. They are based on observed effects and explicit hypothetical assumptions, not on the original trial design. Smaller effects call for larger planning counts under those assumptions, but the illustrations do not tell whether the completed study had a prespecified target or adequate power for its original aims.

Finally, this record highlights why design and analysis details are essential to interpreting clinical-trial summaries. Product labels, analysis populations, missing values, sequence allocation, and the planned handling of repeated measures determine how far descriptive contrasts can support broader conclusions. The reported endpoint data remain informative, but a detailed statistical analysis plan would be needed to evaluate the intended inferential approach.

18. 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 enrollment was 24, and product-level analysis counts range from 23 to 24 for the primary endpoint. This limits the amount of information available for estimating differences and characterizing variability. The analysis population is based on use of a specific product, but reasons for differences in counts are not reported in the registry record.

The intervention labels are generic. Although the study title refers to heated tobacco products and combustible cigarettes, the record does not map Product A, Product B, Product C and Product D to those categories. Consequently, product-level results cannot be interpreted as a direct category comparison based on the registry descriptions alone.

The study is open-label, with no masking. Subjective urge measures may be influenced by participants' awareness of the product being used. The registry record does not report whether or how this possibility was addressed in the study conduct or analysis. The questionnaire scale's range and scoring interpretation are also not reported.

Although the sequences are specified, participant allocation counts by sequence, washout details, and methods for evaluating period or carryover effects are not reported in the registry record. The posted summaries do not include participant-level paired measurements, limiting the ability to assess within-person variability or independently reconstruct a crossover comparison.

The original analysis plan, handling of missing data, multiplicity approach, and sample-size justification are not reported. The inferential comparisons available in this analysis are unadjusted recalculations rather than a documented sponsor analysis. Finally, the primary observation period and confinement schedule address short-term measurements; longer-term outcomes are not reported in the registry record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of Heated Tobacco Products Compared to Combustible Cigarettes — NCT05459857.
• Registry record last updated 2025-02-03; status last verified 2025-01.
• Results first posted 2025-02-03.
• 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.

22. Record Summary

NCT05459857 is a completed randomized, open-label cross-over study sponsored by Imperial Brands PLC. It enrolled 24 adult male or female smokers of combustible cigarettes and describes a screening visit followed by a 5-day confinement period. Participants were assigned to one of four sequences involving Products A–D.

The primary endpoint was baseline-adjusted maximum measured plasma nicotine concentration, reported as a product-level mean and standard deviation. Product D had a higher posted mean than Product A, while the unadjusted recalculated comparisons for Products B and C had confidence intervals including zero. The record also includes three subjective urge-to-smoke outcomes and product-specific safety summaries.

The posted comparisons are unadjusted recalculations from summary statistics. The registry record does not report the original analysis model, crossover adjustments, multiplicity procedure, missing-data method, or original sample-size justification. Product-category mapping for the four labels is not reported in the registry record.