Reduced Exposure to HPHC in Smokers Switching From Cigarettes to Different Versions of THS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Reduced Exposure to HPHC in Smokers Switching From Cigarettes to Different Versions of THS (NCT05599451), a randomized na study. The primary outcome is Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA).

2. Clinical Question

The study was designed to examine biomarkers of exposure to selected harmful and potentially harmful constituents of cigarette smoke. The primary outcome named in the registry record is the concentration of 3-HPMA, expressed as a geometric least squares mean with a 95% confidence interval. The three device arms represent distinct versions of the tobacco heating system; they should not be treated as one combined intervention unless an analysis explicitly does so.

The registry record describes the study’s aim and endpoint, but does not report the Day 5 estimates or comparisons. Thus, the clinical question can be stated, but the posted record does not establish the direction or size of any difference between groups. It also does not report whether the primary question was tested using a prespecified statistical model or how the separate device comparisons were handled together.

3. Trial Design

This was a randomized, controlled, open-label study with four parallel arms. Participants were assigned to use the THS Blade device, THS Induction Mono device, THS Induction Mid device, or continue smoking cigarettes. The registry describes stratified randomization by sex and a quota requiring at least 40% overall for each sex. Enrollment was 91, and the study status is completed.

Each assigned regimen was followed for 5 days in confinement, with ad libitum use between 06:30 AM and 11:00 PM. The three THS groups used their respective devices and regular tobacco sticks. The cigarette group used each participant’s preferred brand of regular, non-mentholated cigarette. The study is described as open-label, so masking was none. The phase is listed as NA.

The primary completion date was 2023-02-04, and the start date was 2022-11-04. These dates describe the trial record, not when results became available. The registry identifies Philip Morris Products S.A. as the sponsor.

Adverse-event group listings include 19 at risk in the cigarette group, 20 in the THS Blade group, 21 in the THS Induction Mono group, 20 in the THS Induction Mid group, and 11 enrolled but not randomized. These are the group counts shown in the safety record; they do not establish the analysis population for the primary endpoint. The registry does not report the number contributing to each primary outcome comparison, reasons for non-inclusion, or the analysis population definition.

The registry record does not report a sample-size justification or a detailed statistical analysis plan. It also does not report specific randomization procedures beyond the sex stratification and quota description.

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

Reasons for not completing this period:

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 Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA), measured over 5 days.

The primary endpoint is the concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) measured in urine and adjusted for creatinine at Day 5. The unit is ng/mg creatinine. The registry describes the outcome as a geometric least squares mean with a 95% confidence interval for each group.

3-HPMA is one of the biomarkers of exposure that the study intended to assess in relation to selected harmful and potentially harmful constituents in cigarette smoke. A urinary biomarker provides a measured indicator of exposure over the relevant period; creatinine adjustment is used to account for differences in urine concentration. The registry record identifies this endpoint but does not report the biological rationale for selecting it as primary, the assay procedures, or the handling of values outside assay limits.

General statistical context: A geometric mean summarizes positive measurements on a multiplicative scale and can be useful when biomarker values are skewed. A geometric least squares mean generally reflects a model-based estimate, but the model, any covariates, and the transformation details are not reported in the registry record. A confidence interval communicates uncertainty around an estimated mean; it does not by itself establish whether a comparison is statistically significant.

No Day 5 group estimates or confidence intervals are reported in the registry record. Therefore, the endpoint definition is available, but its observed values and precision cannot be described from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical context: A parallel-arm randomized design assigns participants to one of several groups and compares outcomes across those groups. Random allocation is intended to reduce systematic differences in baseline characteristics, on average, but it does not guarantee that groups are identical. The registry describes randomization stratified by sex and a minimum quota for each sex overall. Details such as sequence generation, allocation concealment, and implementation are not reported in the registry record.

What does the primary summary measure?

The outcome is stated as a geometric least squares mean. In general, a geometric mean is calculated on a logarithmic scale and returned to the original scale. It is often used for positive measurements whose distribution is skewed, because multiplicative differences may be more meaningful than arithmetic differences. A least squares mean is typically a model-based group summary. The registry does not describe the model used, the variables included in it, or whether any transformations or other adjustments were applied beyond the stated creatinine adjustment of the urine concentration.

The report’s stated precision measure is a 95% confidence interval. In general, a confidence interval gives a range of values compatible with the data under the statistical procedure used. Its width reflects uncertainty, which can depend on variability and the amount of information available. It is not a guarantee that the true value lies in the interval, and it does not alone provide a complete interpretation of a group comparison. The registry does not provide the endpoint intervals or a confidence interval for a between-group contrast.

How should the treatment comparisons be understood?

The clinical question involves three distinct comparisons: each THS device group against continued cigarette smoking. Those are not interchangeable comparisons. A result for one device cannot automatically be attributed to another device, and a combined estimate would require a defined pooling approach. The registry does not report the estimates, test results, or model contrasts for these comparisons. It also does not report whether the analyses were adjusted for baseline biomarker values or other characteristics.

Randomization supports an intention-to-treat comparison when participants are analyzed according to assigned groups, but the registry does not state whether the primary analysis followed that principle. It does not identify whether a per-protocol or other analysis population was used, or how participants who discontinued assigned use were handled. The group counts in the adverse-event record should not be assumed to be the endpoint analysis counts.

What does the planning illustration represent?

The posted planning illustration is described as based on the observed effect, not as the trial’s own design justification. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. Such calculations are planning illustrations: they describe sample sizes associated with specified assumptions and are not observed power. The registry does not report the trial’s own sample-size justification, and there are no primary outcome estimates in the record from which to interpret an observed effect. No planning sample-size result can therefore be used as evidence about the trial’s findings.

In general, planning calculations depend on assumptions about the effect size, variability, allocation, and statistical test. Changing those assumptions can change the sample size needed for a target operating characteristic. The assumptions in an illustration should not be mistaken for the actual design choices unless the registry identifies them as such. Here, the registry explicitly characterizes the illustration as separate from the trial’s own design planning.

What can be said about distributional assumptions?

The primary measure is a geometric summary, but the registry does not report residual diagnostics, distributional assessments, or the statistical model. It is therefore not possible to assess whether model assumptions were checked or whether an alternative analysis was considered. As a general point, skewed biomarker measurements may require methods that reflect their distribution; the appropriate choice depends on the data and the analysis objective, neither of which is documented in sufficient detail in the registry record.

Over-dispersion is a general concern when observed variability exceeds what a model assumes. When relevant, failing to account for it can make uncertainty estimates too small. The registry does not identify the primary endpoint model or report dispersion information, so there is no basis to say whether over-dispersion applied or how it was addressed in this study.

What information is missing for independent checking?

The registry record does not provide group-level primary outcome values, measures of variability, between-group contrasts, confidence intervals, p-values, or analysis details. It also does not report assay methods, data transformations, missing-outcome handling, or the number analyzed for each comparison. Without those elements, readers cannot reproduce the endpoint analysis or check its numerical precision from the registry record alone. The statistical concepts above describe general methods, not confirmed procedures for this trial.

10. Multiplicity, Missing Data and Analysis Populations

The study has three THS device groups, each with a natural comparison against continued cigarette smoking, and the registry lists five outcome measures. It also indicates that the primary outcome has several categories or time points and was not reduced to one comparison. These features raise questions about multiplicity: when several hypotheses or endpoints are tested, the chance of at least one apparently notable result can increase if each test is interpreted independently.

General statistical context: A prespecified multiplicity strategy can define how multiple comparisons are handled, for example by adjusting the testing procedure or identifying a primary contrast. The registry record does not report whether such a strategy was planned or used. It does not identify a hierarchy among the device comparisons or explain how the several outcome categories or time points relate to the primary question. No inference about adjustment should be made from the fact that the outcome was not reduced to one comparison.

The registry does not report missing-data methods, the number with usable Day 5 measurements, or reasons for missing outcome values. It also does not describe imputation, sensitivity analyses, or whether participants with incomplete data were excluded. These details matter because missing measurements can affect the population represented by an analysis and the precision of its estimates.

Analysis populations are not reported in the registry record. In particular, it is not stated whether the primary analysis included all randomized participants according to assignment or only those with available measurements or adherence to the assigned regimen. The safety listings include an enrolled-but-not-randomized group, but they do not define the primary endpoint population. These omissions limit interpretation of the intended estimand and the extent to which the endpoint analysis would reflect the randomized groups.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry’s safety listings show zero serious adverse events in each group for which safety counts are reported: the cigarette group, the THS Blade group, the THS Induction Mono group, the THS Induction Mid group, and the enrolled-but-not-randomized group. Deaths are also listed as zero in each of these groups. These figures are counts in the registry record, not estimates of comparative risk.

Other adverse events are reported for 0 of 19 in the cigarette group, 9 of 20 in the THS Blade group, 1 of 21 in the THS Induction Mono group, 5 of 20 in the THS Induction Mid group, and 0 of 11 in the enrolled-but-not-randomized group. These are the recorded affected and at-risk counts. The registry does not provide event terms for the affected participants, severity details for the other events, or group-comparison analyses.

A zero count in a group means no events of that recorded category were listed for the group; it does not establish that the underlying risk is zero. Group sizes are limited, and the registry record does not supply estimates of uncertainty for these safety counts. The safety information should therefore be read descriptively. It does not establish that one group is safer than another, and it does not characterize risks beyond the reported study period.

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

The registry record describes a short randomized comparison of three tobacco heating system versions with continued cigarette smoking and identifies urinary 3-HPMA at Day 5 as the primary endpoint. It also records some adverse-event counts. These registry entries describe the study’s design and what the registry lists, but they do not provide the primary outcome estimates needed to assess the exposure comparison.

The study objective was to examine reductions in biomarkers of exposure. An objective is not a result. Because the registry does not report group means, confidence intervals, or comparison tests for the primary endpoint, it is not possible to say whether 3-HPMA was lower, higher, or similar in any device group compared with the cigarette group. The absence of those results also prevents assessment of the magnitude and precision of any differences.

Even a reported difference in this biomarker would address exposure over the recorded 5-day period, not by itself establish changes in disease risk, long-term health outcomes, or effects under use outside confinement. The registry does not report clinical outcome measures or longer-term follow-up results. The endpoint should therefore be understood as a biomarker measure, not as a direct measure of clinical benefit or harm.

The safety counts are descriptive and do not support a comparative safety conclusion. Zero recorded serious adverse events in the listed groups should not be interpreted as proof that serious events cannot occur. Likewise, differences in the counts of other adverse events cannot be interpreted as treatment effects without fuller event information and appropriate analysis.

The record’s completed status means the trial is listed as completed; it does not resolve the absence of posted outcome analyses. The most defensible reading is therefore bounded: the registry documents the intended comparison, study conduct, primary endpoint definition, and selected safety counts, while leaving the central primary outcome result and important analysis details unreported.

13. Why This Trial Matters Statistically

This trial raises several important statistical questions because it compares three distinct devices with a common cigarette group. Each device contrast is scientifically distinct, and the interpretation depends on the estimates and uncertainty for each comparison. Without those results, readers cannot judge whether the groups separated on the primary biomarker or how consistently the comparisons pointed in the same direction.

The endpoint also illustrates the role of measurement scale. A urinary biomarker adjusted for creatinine is summarized using a geometric least squares mean, a form that can be appropriate for positive and skewed measurements. But interpretation depends on the model and on the reported contrasts, not just the label of the summary statistic. The registry record does not provide enough analysis detail to evaluate those choices.

Multiplicity is another central issue. Three device comparisons and several listed outcome measures create more than one possible result to interpret. A transparent statistical plan can clarify which question is primary and how secondary comparisons should be treated. The registry does not report such a plan, so the family of intended inferences cannot be reconstructed from the record.

Finally, a planning illustration based on an observed effect should be kept separate from the trial’s original design justification and from evidence of a result. Planning values do not describe observed power, and they do not replace the actual endpoint estimates. The record’s missing outcome analyses make that distinction particularly important: statistical planning context cannot answer the clinical comparison when the observed results are not reported.

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 main trial-specific limitation for interpretation is that the registry record does not report the primary endpoint estimates or any endpoint analyses. Although the primary measure and time point are described, there are no group values, confidence intervals, or statistical comparisons available to characterize the observed findings. The record lists five outcome measures but does not give the outcome details needed to interpret them.

The primary comparison is not reduced to one contrast, and the record does not explain the categories or time points involved. It also does not state how the three device-versus-cigarette comparisons were prioritized or whether any multiplicity approach was used. This leaves the intended inferential framework unclear.

Important analytical details are not reported, including the model specification, analysis population, handling of missing endpoint measurements, and the number contributing to each comparison. The record does not describe assay procedures, baseline outcome values, or the approach to measurements outside assay limits. These omissions prevent independent assessment of the endpoint analysis.

The study was open-label and conducted in confinement over 5 days. The registry does not report longer-term outcome data, so the endpoint description concerns the short period recorded. The described setting and duration should be considered when assessing how broadly any findings might apply, but the missing outcome results prevent evaluation even within that setting.

Safety information is also limited to counts. Serious adverse events and deaths are listed as zero across the recorded groups, while other adverse events are given as group counts. Event descriptions and comparative analyses are not reported. The registry’s planning illustration is explicitly separate from the trial’s own design justification and cannot fill these reporting gaps.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Reduced Exposure to HPHC in Smokers Switching From Cigarettes to Different Versions of THS — NCT05599451.
• Registry record last updated 2024-09-20; status last verified 2024-05.
• Results first posted 2024-09-20.
• 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

The registry record describes NCT05599451, a completed randomized, controlled, open-label, four-arm parallel study sponsored by Philip Morris Products S.A. Enrollment was 91. Participants were assigned to a THS Blade device, THS Induction Mono device, THS Induction Mid device, or continued cigarette smoking for 5 days in confinement. Randomization was stratified by sex, with a quota for each sex of at least 40% overall.

The primary endpoint was urinary 3-hydroxypropylmercapturic Acid (3-HPMA), adjusted for creatinine, at Day 5, summarized as a geometric least squares mean with a 95% confidence interval. The registry record does not report endpoint estimates or analyses. It lists five outcome measures and zero analyses, and does not report the analysis population, missing-data methods, or multiplicity strategy.

Safety listings report zero serious adverse events and zero deaths in each group, alongside counts of other adverse events. These are descriptive counts; the registry does not provide comparative safety analyses. The central primary biomarker result and its precision are not reported in the registry record.