Reduction of Exposure, Inflammation, and Oxidative Stress Following at Least 2 Years of Switching to THS Use Compared to Cigarette Smoking: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Reduction of Exposure, Inflammation, and Oxidative Stress Following at Least 2 Years of Switching to THS Use Compared to Cigarette Smoking (NCT05385055), a registered phase not stated study. The primary outcome is Carboxyhemoglobin (COHb) in Blood.

2. Clinical Question

3. Trial Design

The registry describes a cross-sectional, multi-center, multi-regional study with three groups: current cigarette smokers, THS users with a minimum of 2 years of THS use, and former cigarette smokers with a minimum of 2 years of smoking abstinence. Participants were enrolled and matched by region (Asia, Europe), age, sex, and average daily product consumption over the last 2 years as self-reported. The listed interventions are THS use, cigarette smoking, and smoking abstinence, each categorized as “OTHER.”

Cross-sectional design means, in general, that measurements are taken at a specified assessment rather than following participants through a randomized treatment period. Here the primary COHb measurement is described as occurring when a subject visits the study site on day 1. That does not establish when product use began for every participant beyond the group definitions, nor does it show changes within individuals over time. The comparison therefore concerns groups with different reported smoking or THS histories; it does not by itself establish that the group differences were caused by those histories.

The study status is COMPLETED. The registry lists a start date of 2022-06-13 and a primary completion date of 2023-12-27. Enrollment is listed as 974, but this is not the reported count analyzed for the primary endpoint. The group-specific safety populations are recorded separately. The number of participants with an evaluable COHb result in each group, exclusions by group, and the final endpoint analysis population are not reported in the registry record.

The record’s description of the analysis population refers to “all randomized subjects,” while the study is described as a cross-sectional three-group study and the registry notes that this was not a randomized comparison and that allocation was not stated. This wording does not resolve how participants entered the groups. The method of recruitment, matching implementation, and any adjustments used to account for matching 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 (Modified Per-Protocol Analysis Set \[mPP\]) consisted of all randomized subjects, with at least one product use experience and at least one valid non-safety assessment, and excluded subjects with major deviations impacting the evaluability of the objectives. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

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: The Modified Per-Protocol Set (mPP) is a subset of the Full Analysis Set (FAS: enrolled subjects who did not screen fail and were deemed eligible based on group allocation from the tobacco and nicotine use history questionnaire) and excludes all subjects with major deviations impacting the evaluability of the primary objective, and all subjects not belonging to a complete triplet (with one current smoker, one former smoker, and one THS user) used for matching.

6. Primary Endpoint

The registry lists the primary outcome as Carboxyhemoglobin (COHb) in Blood, measured over Measured when subject visits study site on day 1..

The primary endpoint is carboxyhemoglobin (COHb) in blood, measured as a percentage of total hemoglobin saturated with carbon monoxide. The assay is described as being performed on whole blood. The reported statistical measure is a geometric least-squares mean, with a 95% confidence interval. The assessment is taken at the study-site visit on day 1.

COHb is relevant to the stated study objective because the title and description concern reduction in exposure to key toxicants, and the endpoint quantifies the proportion of hemoglobin saturated with carbon monoxide. It gives a continuous biomarker measure for comparing the groups at assessment. It is not, by itself, a measure of every toxicant, inflammation, oxidative stress, or a clinical health outcome. The endpoint definition therefore sets the scope of the primary question: it concerns this blood measure, not all outcomes named in the study title.

In general, a confidence interval describes uncertainty around an estimated quantity under the analysis assumptions. Its width helps readers judge precision, while its location describes the range of estimates compatible with the data and method. The registry record identifies the intended summary and interval but does not report the COHb estimates, confidence limits, or group contrasts. Thus, the endpoint’s observed magnitude, direction, and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a geometric least-squares mean represent?

The registry specifies a geometric least-squares mean for COHb. In general, a least-squares mean is an estimate derived from a statistical model rather than a simple arithmetic average. It can represent a model-adjusted group mean, depending on the model and the covariates included. The registry record does not report the model specification, its covariates, or the method used to obtain the geometric estimate. It is therefore not possible to determine from the record which adjustments, if any, underpin the reported measure.

In general, geometric means are used for measurements analyzed on a logarithmic scale and then expressed back on the original scale. Such summaries can be useful when values are right-skewed or when comparisons are naturally expressed multiplicatively. That is general statistical context, not a description of the trial’s undocumented analysis steps. The record names the geometric least-squares mean, but does not state whether values were transformed, how model assumptions were checked, or how values at any limits of measurement were handled.

How should the confidence interval be read?

The registry specifies a 95% confidence interval around the primary summary. In general, a confidence interval conveys the statistical uncertainty in an estimate under the model and sampling assumptions. A narrower interval indicates greater precision than a wider interval, while the estimate and the interval together describe the location and uncertainty of the result. The interval does not include every source of uncertainty: for example, it cannot remove bias from unmeasured differences between groups or uncertainty caused by an unsuitable model.

The registry record does not give the COHb confidence limits or estimates. It also does not report a confidence interval for a particular group contrast, a test statistic, or a p-value. Consequently, there is no numerical interval to interpret, and statistical significance cannot be assessed from the record.

Why does the comparison structure matter?

The groups were matched by region, age, sex, and self-reported average daily product consumption over the last 2 years. In general, matching is intended to make groups more comparable on selected characteristics. It does not make a non-randomized comparison equivalent to a randomized experiment, and it does not control characteristics that were not matched or measured. The registry record does not report how matching was implemented, whether the analysis accounted for matching, or whether group characteristics were balanced after enrollment.

The comparison is cross-sectional, and the endpoint is measured at the site visit on day 1. In general, cross-sectional measurements can describe differences between groups at assessment but do not establish that a group’s exposure history caused those differences. The registry also does not report a within-person baseline measurement for the primary endpoint. The study’s group definitions and matching information are therefore essential context when interpreting any future-reported contrast.

What can planning calculations tell readers?

Any sample-size figures associated with the results are planning illustrations based on the observed effect, not the trial’s own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. In general, a planning calculation estimates the sample size needed under chosen assumptions for a target power. It does not show the power actually achieved in a completed study. These illustrations must not be described as observed power.

The assumptions also do not establish that the study itself used equal allocation, the normal approximation, or that significance level for its original design. The registry record does not report the protocol’s sample-size justification or a prospective power calculation. Moreover, the observed COHb effect needed to evaluate any effect-based planning illustration is not reported in the registry record. Time-to-event planning summaries refer to total events, while other such summaries refer to participants per arm; those conventions do not replace the underlying analysis results.

Why can dispersion affect inference?

The primary endpoint’s stated dispersion measure is a confidence interval, not a standard deviation or a model for over-dispersion. In general, over-dispersion arises when variability in data exceeds what a chosen statistical model assumes. If it is ignored where relevant, standard errors and confidence intervals may be too small, making estimates appear more precise than warranted. That general issue cannot be tied to this trial’s analysis because the registry record does not describe the model, residual variability, distributional checks, or any over-dispersion assessment. The available method description is limited to the geometric least-squares mean and 95% confidence interval.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies COHb as the primary endpoint and lists secondary outcomes including HDL-C, sICAM-1, 11-DTX-B2, AIx, and post-bronchodilator FEV1 %Predicted. It reports 22 outcome measures and 44 analyses. Considering multiple endpoints or comparisons creates a multiplicity issue: in general, testing many hypotheses can increase the chance of at least one apparently notable result arising by chance. The registry record does not report whether tests were prioritized, whether a multiplicity adjustment was used, or how any such procedure was defined.

The statistical analysis plan, including the planned group contrasts, model covariates, significance thresholds for the endpoint analyses, and handling of interim analyses, is not reported in the registry record. The registry’s planning illustration assumptions do not establish the analysis plan used for the trial. No endpoint estimates or p-values are reported, so the statistical evidence across the primary and secondary outcomes cannot be evaluated.

The analysis population is described as a Modified Per-Protocol Analysis Set comprising subjects with at least one product use experience and at least one valid non-safety assessment, excluding subjects with major deviations affecting evaluability. The number included in this set, endpoint-specific missingness, and reasons for missing measurements are not reported in the registry record. The method for handling missing data, including whether any imputation was used, is also not reported. Without these details, it is not possible to assess whether the analyzed participants differed from those excluded or whether missingness could have affected estimates.

The population description refers to randomized subjects, while the registry separately describes a non-randomized comparison with allocation not stated. The record does not explain this wording or clarify the analysis populations for each comparison. These omissions limit assessment of multiplicity, missing-data risk, and the relation between the enrolled groups and the analyses.

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.

The registry lists serious adverse event figures separately for Cigarette, THS User, and Former Smoker. For each listed group, the number at risk for serious adverse events matches the number at risk for other adverse events: 322 for Cigarette, 329 for THS User, and 323 for Former Smoker. The recorded number affected by serious adverse events is 0 in each group, and the recorded number affected by other adverse events is also 0 in each group. Deaths are recorded as 0 in each group. No top serious adverse event terms are listed.

These are the registry’s posted counts, not an estimate of comparative safety risk. In general, a zero recorded count means that no affected participants are reported in that category for the listed group; it does not prove that an event is impossible or that all relevant harms have been ruled out. The record does not provide event-level descriptions, follow-up duration for safety collection, ascertainment procedures, or a discussion of completeness. It also does not report comparative statistical analyses of adverse events. The group figures should therefore be read as descriptive registry entries, not as evidence that the groups have equivalent safety profiles.

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

This record describes a cross-sectional comparison of COHb among current cigarette smokers, THS users with a minimum of 2 years of THS use, and former cigarette smokers with a minimum of 2 years of smoking abstinence. It specifies the blood measure, its unit, the geometric least-squares mean, and the 95% confidence interval. It also describes matching on region, age, sex, and self-reported average daily product consumption over the last 2 years.

The record does not report the COHb estimates or confidence intervals. It therefore does not show the size, direction, or precision of the primary comparison. The study title expresses an intended investigation of reduced exposure, inflammation, and oxidative stress; it is not a substitute for numerical findings. Although the registry lists secondary outcomes related to several measures, their results are not reported in the registry record either.

Even with complete numerical results, the stated cross-sectional, non-randomized comparison would need to be interpreted as an association between group membership and measurements at assessment. Matching can address selected characteristics, but the record does not establish comparability on all possible factors or describe the analysis adjustment. A group difference would not, by itself, demonstrate that a product change caused that difference. The registry’s wording about randomized subjects in the analysis-set description is also not reconciled with its statement that allocation was not stated and the comparison was not randomized.

The listed safety counts record zero affected participants and zero deaths in each group, but those descriptive entries do not establish the absence of all harms or equivalence between groups. Details on safety collection and comparative analyses are not reported in the registry record.

The defensible conclusion from the posted information is therefore limited: the registry describes the study design and intended endpoints, but does not provide the numerical results required to judge the primary comparison. It cannot support a conclusion about whether COHb differed, how precisely any difference was estimated, or whether any difference was attributable to the group exposure history.

13. Why This Trial Matters Statistically

This study raises several statistical issues that matter when interpreting biomarker comparisons. The groups are defined by current smoking, sustained THS use, or smoking abstinence, and the study is cross-sectional rather than a randomized comparison. That design makes the distinction between a measured group difference and a causal treatment effect especially important. The registry reports matching on region, age, sex, and self-reported average daily product consumption over the last 2 years, but does not describe how matching was implemented or incorporated into the analysis.

The primary endpoint is a continuous blood measure summarized as a geometric least-squares mean with a 95% confidence interval. Readers would need the estimates and intervals to assess both the magnitude and precision of any group differences. Those results are not reported in the registry record. In their absence, the stated endpoint and analysis summary describe what was intended to be evaluated, but not what the data indicate.

Multiplicity also matters because the record lists 22 outcome measures and 44 analyses. In general, multiple analyses require a clear strategy for prioritizing outcomes or interpreting uncertainty across comparisons. The registry record does not report a multiplicity approach or the statistical analysis plan. The analysis population and missing-data details are also incomplete, and the record’s use of “randomized subjects” is not reconciled with the stated non-randomized comparison.

Finally, planning illustrations should be distinguished from evidence about the completed study. Their stated assumptions do not establish the trial’s design rationale or observed power. Without the observed endpoint estimates and analysis details, readers cannot assess whether the sample was informative for the primary question. These features make transparent reporting of estimates, uncertainty, populations, and analysis choices central to interpreting the study.

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 limitation of the registry information is that it does not report the numerical primary endpoint results. COHb group estimates, confidence limits, between-group contrasts, and statistical tests are not reported in the registry record. The same is true for results of the listed secondary outcomes. Consequently, the effect’s direction, magnitude, and precision cannot be evaluated from the posted record.

The study is described as cross-sectional and not a randomized comparison. Although matching is reported for region, age, sex, and self-reported average daily product consumption over the last 2 years, the registry does not report the matching procedure, group balance, or model adjustments. Residual differences between groups may remain, and the record does not provide enough analysis detail to assess them. The method of group allocation is not stated.

There is an unresolved wording issue: the analysis population description refers to randomized subjects, while the design description says the comparison was not randomized and allocation was not stated. The record does not clarify this discrepancy. The enrollment figure does not establish the number analyzed for COHb; endpoint-specific analysis counts and exclusions are not reported.

Further limitations include missing information on the statistical analysis plan, missing-data methods, multiplicity handling, and how the analysis accounted for the multi-regional and matched design. Safety counts are posted, but methods and duration of safety ascertainment are not reported. The record also does not provide the protocol’s sample-size justification. These gaps limit independent assessment of the results and prevent a detailed evaluation of precision, bias, and robustness.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Reduction of Exposure, Inflammation, and Oxidative Stress Following at Least 2 Years of Switching to THS Use Compared to Cigarette Smoking — NCT05385055.
• Registry record last updated 2026-05-08; status last verified 2026-05.
• Results first posted 2026-05-08.
• 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

NCT05385055 is a completed cross-sectional, multi-regional study sponsored by Philip Morris Products S.A. The registry lists enrollment of 974, a start date of 2022-06-13, and a primary completion date of 2023-12-27. The groups were current cigarette smokers, THS users with a minimum of 2 years of THS use, and former cigarette smokers with a minimum of 2 years of smoking abstinence. Participants were matched by region, age, sex, and self-reported average daily product consumption over the last 2 years.

The primary endpoint is blood COHb, expressed as a percentage of total hemoglobin saturated with carbon monoxide and assessed at the site visit on day 1. It is summarized as a geometric least-squares mean with a 95% confidence interval. The registry record does not report numerical primary or secondary outcome results. It lists 22 outcome measures and 44 analyses, but does not report the statistical analysis plan, multiplicity approach, or missing-data methods. The safety entries record zero serious adverse events, other adverse events, and deaths in each listed group.