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 Pharmacokinetics and Pharmacodynamics, Safety and Tolerability of P3P (NCT03369340), a randomized na study. The primary outcome is Plasma Nicotine Concentration-time Profile.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03369340 |
| Phase | NA |
| Condition | Pharmacokinetics |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 19 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Philip Morris Products S.A. |
| Results posted | Yes |
2. Clinical Question
Population
Healthy adult smokers were enrolled in a single-center study. The registry record lists an enrollment of 19; the primary outcome description refers to 18 randomized subjects, with baseline correction possible for 16 of them.
Intervention
The study evaluated four P3P variants, identified as P3P 1, P3P 2, P3P 3, and P3P 4. The variants differed in nicotine aerosol particle size, nicotine concentration, and whether a flavoring system was present. Product use involved a fixed puffing regimen and an ad libitum period.
Comparator
Each participant was exposed to all four variants in a randomized crossover sequence. P3P 3 was used on Day 1 for all sequences; the order of P3P 1, P3P 2, and P3P 4 varied over Days 2, 3, and 4. The registry record does not describe a separate control product or a no-product comparison.
Primary question
The primary question was how plasma nicotine concentrations changed over time after use of the four variants under the fixed puffing regimen, after correction for baseline nicotine levels. The registry record also lists pharmacodynamic outcomes, including cigarette craving, and safety and tolerability assessments, but does not report comparative results for these outcomes.
3. Trial Design
This was a single-center, open-label, randomized crossover study. In a crossover design, the same participant receives multiple study conditions in a planned order, allowing comparisons that account for stable differences between participants. Here, the four conditions were P3P 1 through P3P 4. The registry record describes six possible product sequences. Every sequence began with P3P 3 on Day 1, followed by a randomized order of the other three variants on Days 2, 3, and 4.
The study enrolled 19 participants. The primary outcome description states that 18 subjects were randomized and that baseline correction of nicotine concentrations could be performed for 16 of those subjects. The registry record does not explain the difference between the overall enrollment and the number referenced in the primary outcome population description, or why baseline correction was unavailable for some participants.
Participants used each product according to a fixed puffing regimen and also had an ad libitum use period. The primary outcome was the plasma nicotine concentration-time profile after the fixed puffing regimen. The listed secondary outcomes include peak, time-to-peak, trough, average, and area-under-the-curve measures for plasma nicotine, as well as craving assessments during and after product use. The study description also identifies subjective and behavioral assessments and human puffing topography as areas of evaluation.
The registry lists the study as completed, with a phase classification of NA. It does not report a masking procedure; the study is described as open-label. The registry record does not provide the rationale for the selected sequence structure, a washout description, or further details on the study schedule beyond the product days and the sampling time points.
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: On Day 1, 19 subjects were enrolled and exposed to "P3P 3" before randomization. One enrolled subject withdrew after P3P 3 use before randomization. 18 subjects were randomized.
Day 2
| Stage | Product Sequence 1 | Product Sequence 2 | Product Sequence 3 | Product Sequence 4 | Product Sequence 5 | Product Sequence 6 |
|---|---|---|---|---|---|---|
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Day 3
| Stage | Product Sequence 1 | Product Sequence 2 | Product Sequence 3 | Product Sequence 4 | Product Sequence 5 | Product Sequence 6 |
|---|---|---|---|---|---|---|
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Day 4
| Stage | Product Sequence 1 | Product Sequence 2 | Product Sequence 3 | Product Sequence 4 | Product Sequence 5 | Product Sequence 6 |
|---|---|---|---|---|---|---|
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Baseline correction of nicotine concentrations could be performed for 16 out of the 18 randomized subjects.
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.
| Characteristic | Unit | Safety Population |
|---|---|---|
| Participants analysed | 19 | |
| Age, Continuous | years | 35.4 (SD 9.03) |
| Sex: Female, Male: Female | Participants | 10 |
| Sex: Female, Male: Male | Participants | 9 |
| 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 | 0 |
| Race (NIH/OMB): White | Participants | 19 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Body weight (kg) | kilograms | 72.3 (SD 12.4) |
| Height (cm) | centimetres | 171 (SD 12.6) |
| BMI (kg/m^2) | kg/m^2 | 24.6 (SD 2.72) |
6. Primary Endpoint
The registry lists the primary outcome as Plasma Nicotine Concentration-time Profile, measured over Derived from multiple blood sampling (measured at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours post-product use) on Days 1, 2, 3 and 4.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | ng/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the plasma nicotine concentration-time profile for the four P3P variants, measured in ng/mL. The registry describes the values as geometric means with 95% confidence intervals. Blood sampling was scheduled at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours after product use on Days 1, 2, 3, and 4. The stated purpose was to measure the profile after the fixed puffing regimen, with baseline nicotine levels corrected.
A concentration-time profile describes how measured nicotine levels change over the sampling period rather than reducing the response to a single measurement. It can therefore characterize the course of observed concentrations at the specified times. The registry also lists individual summary measures, including peak and trough concentrations, time to peak, and area under the concentration-time curve, as secondary outcomes. These measures capture different aspects of the profile and are not interchangeable.
Geometric means are a way to summarize measurements on a multiplicative scale, and a confidence interval conveys uncertainty around an estimate. These are general statistical explanations; the registry record does not report the actual concentration estimates or confidence intervals for the primary endpoint. The endpoint is described, but the posted record does not provide results that would permit a comparison of the variants’ concentration-time profiles.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the outcomes and design but does not report primary endpoint estimates, confidence intervals, or statistical comparisons. It therefore does not establish how the plasma nicotine concentration-time profiles differed among P3P 1, P3P 2, P3P 3, and P3P 4. The posted results also do not give values for the listed secondary pharmacokinetic or craving outcomes. Any interpretation of the relative magnitude, direction, or precision of product differences would require results that are not reported in the registry record.
The primary endpoint was planned as a profile with measurements at multiple times, rather than as one prespecified numeric contrast in the available record. A profile can show the pattern of concentrations across sampling times, while a single summary such as peak concentration or area under the curve answers a narrower question. The registry lists several such summaries as secondary outcomes, but their estimates and uncertainty are not reported. The record also indicates 18 outcome measures and no analyses. As a result, there are no reported analysis estimates from which to assess statistical uncertainty or the strength of evidence for differences.
For context, a confidence interval is a range expressing uncertainty around an estimated quantity under the assumptions of the analysis. A narrower interval generally indicates greater precision than a wider interval, but interpretation also depends on the estimate, the outcome scale, and the study question. No primary endpoint confidence intervals are reported, so precision cannot be assessed from the registry record. The listed 95% confidence interval describes the planned form of reporting, not a result in itself.
The crossover structure means participants were exposed to all variants, which can support within-participant comparisons. In general, such comparisons can reduce the influence of stable differences between people. But interpretation also depends on sequence, period, carryover, and the statistical model used. The registry record does not report the analysis model or how these design features were handled. It also does not report results by sequence or period.
The safety results include zero serious adverse events in each listed product group and zero deaths. Other adverse events are counted, but the registry record does not provide their terms, severity, or relationship to product use. These counts are descriptive and should not be treated as comparative evidence of safety. The record does not report inferential analyses for safety or the criteria used to classify events.
Overall, the posted information supports a description of the planned comparisons and the recorded safety counts, but not a conclusion about the direction or size of pharmacokinetic differences. It also does not allow a quantitative assessment of uncertainty, statistical significance, or the clinical importance of any possible differences.
9. Statistical Methods Explained
The registry record describes a randomized, open-label crossover study with four product conditions and a primary outcome measured repeatedly over time. It lists the endpoint summary as geometric means with 95% confidence intervals. It does not report the statistical analysis plan, the model used for the repeated measurements, or any numerical analysis results. The explanations below describe general statistical concepts relevant to this design; they do not establish which methods were applied in this study.
What does a crossover design compare?
In a crossover design, each participant receives more than one condition, and outcomes can be compared within the same participant. This can be useful when differences between people contribute substantial variation, because each participant can serve as their own reference. The registry lists six sequences for exposure to the products: P3P 3 was used on Day 1, and the other three products were assigned in varying orders over the following days.
Within-participant comparisons do not remove every source of uncertainty. Responses may vary with the order or timing of product exposure, and an earlier condition may affect a later measurement. Period effects, sequence effects, and carryover are general considerations for crossover trials. Whether these were assessed, and how they were handled, is not reported in the registry record. The record also does not describe a washout period.
Why measure a concentration-time profile?
A concentration-time profile consists of measurements collected at multiple times after exposure. In this study, plasma nicotine sampling was scheduled at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours after product use on Days 1, 2, 3, and 4. Repeated measurements can describe the pattern of concentrations over the sampled period, while summary measures such as peak concentration or area under the curve condense selected features of that pattern.
The registry describes geometric means for the primary profile. A geometric mean summarizes values using a multiplicative scale and is often used when the distribution is not well represented by an arithmetic mean. This is a general explanation; the registry does not state why this summary was selected or describe the distribution of the study measurements. It also does not report the model used to estimate the geometric means.
What do confidence intervals convey?
A confidence interval expresses uncertainty around an estimate. The registry specifies 95% confidence intervals for the primary endpoint, but does not report the actual intervals. Without estimates and intervals, readers cannot judge the precision of the profile or the degree of overlap between product estimates. A confidence interval is not, by itself, a probability statement that a particular fixed interval contains the true value; its interpretation is tied to the statistical procedure used to construct it.
Why can over-dispersion matter?
Over-dispersion is a general issue that arises when observed variability exceeds what a chosen statistical model expects. If that extra variability is ignored, standard errors and confidence intervals can be too small, and tests can appear more decisive than warranted. The endpoint in this study is a continuous concentration measure, and the registry record does not report whether over-dispersion was relevant or how variability was modeled. This concept is therefore background rather than a description of a method known to have been used in this analysis.
What can be inferred from the analysis record?
The registry lists 18 outcome measures and zero analyses. The primary outcome is described, but no estimated values, confidence intervals, or statistical tests are reported. The record does not state whether comparisons were adjusted for baseline, beyond specifying that baseline nicotine levels were to be corrected for the primary profile. It also does not state whether the correction or subsequent analysis used a particular statistical model.
For planning, sample-size calculations depend on choices such as the target effect, variability, significance level, power, and allocation. The registry’s sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are not observed power and do not establish the basis for the trial’s original design. The registry record does not report the study’s own sample-size justification. Since the primary outcome has multiple time points and is not reduced to one comparison in the record, a single sample-size interpretation cannot be inferred from the endpoint description alone.
These distinctions matter because a design description and a planned summary are not the same as an analysis result. To evaluate a product contrast statistically, readers would need the estimates, uncertainty measures, analysis model, and relevant handling of repeated measures and missing data. Those details are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The primary endpoint consists of a concentration-time profile with multiple sampling times, and the registry also lists numerous secondary outcomes, including several pharmacokinetic summaries and craving measures. When several outcomes, time points, or contrasts are examined, the chance of obtaining an apparently notable result by chance can increase. General approaches to this issue include defining a primary comparison in advance, using a hierarchy of tests, or adjusting inference across multiple comparisons. The registry record does not report whether any multiplicity strategy was prespecified or applied.
The record does not provide a statistical analysis plan, an analysis model, or results for the listed outcomes. It therefore does not establish which comparisons were tested, whether analyses were exploratory or confirmatory, or how any multiplicity was addressed. The registry identifies 18 outcome measures and zero analyses, so no inferential output is available to assess.
For the primary endpoint, baseline correction could be performed for 16 out of the 18 randomized subjects. The reason correction was unavailable for the remaining subjects is not reported in the registry record. The record does not state whether those participants were excluded from the primary analysis, how missing baseline measurements or follow-up samples were handled, or whether any imputation method was used.
The safety denominators are 19 for P3P 3 and 18 for each of the other products. The registry does not explain the difference in these denominators or report further analysis populations, such as a defined per-protocol population. Enrollment, randomization, endpoint availability, and safety exposure counts are distinct concepts; the available record does not reconcile them. Accordingly, the extent and possible effect of missing data cannot be evaluated.
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 |
|---|---|---|---|
| Safety Population (P3P 1) | 0 | 18 | 0.0% |
| Safety Population (P3P 2) | 0 | 18 | 0.0% |
| Safety Population (P3P 3) | 0 | 19 | 0.0% |
| Safety Population (P3P 4) | 0 | 18 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Safety Population (P3P 1) | 0 of 18 |
| Safety Population (P3P 2) | 0 of 18 |
| Safety Population (P3P 3) | 0 of 19 |
| Safety Population (P3P 4) | 0 of 18 |
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 |
|---|---|
| Safety Population (P3P 1) | 4 of 18 |
| Safety Population (P3P 2) | 5 of 18 |
| Safety Population (P3P 3) | 4 of 19 |
| Safety Population (P3P 4) | 3 of 18 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Safety Population (P3P 1) | Safety Population (P3P 2) | Safety Population (P3P 3) | Safety Population (P3P 4) |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | 2 of 18 | 2 of 18 | 2 of 19 | 2 of 18 |
| Nausea | Gastrointestinal disorders | 3 of 18 | 1 of 18 | 2 of 19 | 0 of 18 |
| Vomiting | Gastrointestinal disorders | 0 of 18 | 1 of 18 | 1 of 19 | 1 of 18 |
| Lymphocytes increased | Investigations | 1 of 18 | 1 of 18 | 0 of 19 | 0 of 18 |
| Dyspepsia | Gastrointestinal disorders | 0 of 18 | 1 of 18 | 0 of 19 | 0 of 18 |
| Headache | Nervous system disorders | 0 of 18 | 0 of 18 | 1 of 19 | 0 of 18 |
| Neutrophils decreased | Investigations | 0 of 18 | 0 of 18 | 1 of 19 | 0 of 18 |
| Nasopharyngitis | Infections and infestations | 0 of 18 | 1 of 18 | 0 of 19 | 0 of 18 |
The registry lists safety counts separately for each product. Among 18 participants at risk for P3P 1, there were zero serious adverse events and zero deaths; the count for other adverse events was 4. For P3P 2, 18 were at risk, with zero serious adverse events, zero deaths, and 5 other adverse events. For P3P 3, 19 were at risk, with zero serious adverse events, zero deaths, and 4 other adverse events. For P3P 4, 18 were at risk, with zero serious adverse events, zero deaths, and 3 other adverse events.
These are descriptive counts. They do not show whether the other events were mild or severe, whether they were considered related to product use, or whether the same participant experienced events in more than one product period. The registry record does not report those details or provide a statistical comparison of the groups. The different at-risk counts should also be kept in view when reading the event counts. Zero serious events in these recorded groups does not establish that serious events are impossible or that the products have equivalent safety profiles.
12. What the Result Does, and Does Not, Mean
The registry record establishes that investigators planned to study plasma nicotine concentrations over time after use of four P3P variants, along with pharmacodynamic, behavioral, and safety measures. It describes a randomized crossover arrangement in healthy adult smokers and specifies a primary profile endpoint with geometric means and 95% confidence intervals. Those design details clarify the questions the study was intended to address.
They do not show how the products compared. Numerical results for the primary endpoint and the listed secondary outcomes are not reported in the registry record. There are no reported concentration estimates, confidence intervals, or statistical tests with which to assess the size, direction, or precision of a difference. The planned endpoint definition should not be mistaken for evidence that one variant produced a higher or lower concentration profile.
The reported safety counts show zero serious adverse events and zero deaths in each listed product group. Other adverse events were recorded, but their descriptions and severity are not given. These counts do not establish equivalence between products or support a broad conclusion about safety, particularly without event details, comparative analyses, and fuller information about exposure and follow-up.
More generally, a result can be statistically distinguishable without being important to a practical decision, and an imprecise estimate can remain compatible with a range of effects. These are general statistical points; this registry record does not provide estimates that permit either assessment. The posted information supports interpretation of the study’s design and the limited reported event counts, but not a conclusion about the pharmacokinetic or pharmacodynamic performance of the variants.
13. Why This Trial Matters Statistically
This trial is statistically notable for its crossover structure and repeated concentration measurements. Each participant was scheduled to use all four variants, with the order of three variants randomized after P3P 3 on Day 1. In general, within-participant comparisons can make efficient use of data by accounting for stable differences between people. At the same time, repeated periods require attention to order, period, and possible carryover effects. The registry record does not report how these features were addressed analytically.
The primary endpoint is a profile rather than a single measurement. Sampling at multiple times can capture changes in concentration across the observation period, while distinct summaries such as peak concentration, time to peak, and area under the curve describe separate aspects of the data. Because multiple outcomes and time points are involved, transparent reporting of the analysis plan and any multiplicity approach is important for interpreting evidence. Those details are not reported in the registry record.
The record also illustrates why outcome definitions should be distinguished from outcome results. It identifies a geometric-mean profile and 95% confidence intervals but does not report their values or any analyses. Without estimates and uncertainty, readers cannot assess the size or precision of product differences. The safety counts provide a limited descriptive view but do not supply a comparative safety analysis.
Finally, the primary outcome population description notes that baseline correction was possible for 16 out of the 18 randomized subjects. Clear accounting of analysis populations and missing measurements is important in a repeated-measures crossover study. The registry does not explain the unavailable corrections or how missingness was handled, leaving an important aspect of interpretation unresolved.
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 principal limitation of the registry record is that it does not report numerical results for the primary concentration-time profile or the secondary outcomes. The planned summaries and sampling schedule therefore cannot be used to determine the size, direction, or precision of product differences. The record lists zero analyses, so no inferential comparisons are available.
Important statistical details are also absent. The analysis model, treatment of repeated measurements, handling of sequence and period effects, assessment of carryover, and approach to multiplicity are not reported in the registry record. The record does not describe a washout period or provide a statistical analysis plan. Without these details, the intended crossover comparisons cannot be assessed beyond the design description.
Baseline correction could be performed for 16 out of the 18 randomized subjects, but the reason it could not be performed for the others is not reported. The registry does not state how missing observations were handled or identify a full analysis population. It also lists safety denominators of 19 for P3P 3 and 18 for the other variants without explaining that difference.
The study was single-center and open-label, as described in the registry. The record does not provide enough detail to evaluate how these features affected measurement or reporting. The safety information is limited to counts; descriptions, severity, relatedness, and comparative analyses of the other adverse events are not reported. These limitations restrict interpretation to the design and the specific posted counts rather than conclusions about comparative outcomes.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Nicotine Pharmacokinetics and Pharmacodynamics, Safety and Tolerability of P3P — NCT03369340.
- Registry record last updated 2020-01-31; status last verified 2020-01.
- Results first posted 2020-01-31.
- 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.
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18. Record Summary
The registry record describes a completed, single-center, open-label randomized crossover study of four P3P variants in healthy adult smokers. Enrollment was 19. All product sequences began with P3P 3 on Day 1, followed by randomized orders of the remaining variants on Days 2, 3, and 4.
The primary outcome was the plasma nicotine concentration-time profile after a fixed puffing regimen, with baseline correction and geometric means with 95% confidence intervals specified. The record also lists pharmacokinetic, craving, behavioral, and safety outcomes. Baseline correction was possible for 16 out of the 18 randomized subjects. Numerical outcome results and statistical analyses are not reported in the registry record. Safety listings show zero serious adverse events and zero deaths in each product group, alongside counts of other adverse events.