Transdermal Patch CVD 1000: The Effect of Heat on Nicotine Release From Nicotine Patches in Adult Smokers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Transdermal Patch CVD 1000: The Effect of Heat on Nicotine Release From Nicotine Patches in Adult Smokers (NCT02371850), a na phase 4 study. The primary outcome is Measurement of Maximum Serum Concentration (Cmax).

2. Clinical Question

The study concerns nicotine exposure in adult smokers using two transdermal nicotine patches: the reference Nicoderm CQ patch and the generic Aveva patch. The registry describes a sequence in which participants used the Nicoderm patch first and the Aveva patch afterward. Heat was applied during each patch condition at specified times. The primary question was whether maximum serum nicotine concentration, or Cmax, differed across the study conditions.

The study is described as a bioequivalence study, but that label does not establish that the patches were found to be bioequivalent. A conclusion of that kind would require reported outcome estimates and an analysis against prespecified criteria. Those estimates, criteria, and a formal comparison are not reported in the registry record. The design also does not describe an unheated patch condition, so the primary question as recorded is not a direct comparison of heating with no heating.

3. Trial Design

The registry identifies this as a Phase 4, completed study sponsored by the University of Maryland, Baltimore. The recorded start is 2014-10 and primary completion is 2015-04. Ten adult smokers completed the study. It is described as single-group, open-label, nonrandomized, and as a two-way crossover bioequivalence study.

In a crossover design, the same participants receive more than one condition, so each person can contribute measurements under multiple conditions. This can support within-person comparisons because measurements from one participant share characteristics. The registry describes the order as Nicoderm first, followed by Aveva; allocation is listed as NA. Thus, the order was not randomized according to the registry record. A fixed sequence means that patch condition and period occur in the same order, so any change between periods cannot automatically be attributed only to patch type.

The arm description states that participants completed two procedure days with Nicoderm and two procedure days with Aveva. Heat was applied for one hour at hours 4 and 8 after application for each patch condition. The primary outcome timeframe is the four procedure days for each participant. The record does not describe an unheated condition, a washout interval, or additional procedures beyond those stated.

Masking is listed as none, consistent with an open-label study. The registry does not report a separate control group or a randomized treatment sequence. The record also does not report details of a protocol-defined sample-size justification, stopping rule, interim analysis, or analysis plan. Those omissions limit what can be inferred about how the planned design was intended to support a formal comparison.

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: Ten adult smokers between 24 and 44 years of age at the time of enrollment completed the study. The clinical study was an single-group, open-label study. Each subject completed 4 study visits where in-vivo nicotine levels were measured using a reference patch (Nicoderm CQ) and a generic patch (Aveva)

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 Measurement of Maximum Serum Concentration (Cmax), measured over four procedure days for each participant.

The primary endpoint is maximum serum concentration, Cmax, measured in ng/mL. Cmax is the highest measured concentration of a substance in blood or serum over a defined observation period. For a nicotine patch study, it describes the peak serum nicotine level recorded during the measurement schedule; it does not by itself describe the full concentration-time profile.

Cmax is one way to characterize systemic exposure. It is often considered alongside measures that use concentrations across time, such as area under the concentration-time curve, or AUC. The registry lists AUC as a secondary outcome, but does not report its numerical results. A peak measure and a measure of exposure over time answer related but distinct questions, and one does not substitute for the other.

The registry describes the Cmax outcome as a mean with standard deviation and gives the timeframe as four procedure days for each participant. A mean conveys the average measurement in the analysis group; a standard deviation describes the spread of participant measurements around that mean. No numerical mean, standard deviation, confidence interval, or comparison estimate for Cmax is reported in the registry record. Therefore, the endpoint definition is available, but the magnitude and precision of the observed Cmax results cannot be assessed from the recorded results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods that can be interpreted are limited by the information in the registry record. The design description and outcome definition are present, but numerical efficacy results and a reported statistical analysis are not. The explanations below distinguish general statistical principles from what this record documents.

What does Cmax summarize?

Cmax is the highest serum concentration measured during a specified observation period. In general, a maximum is useful for describing peak exposure, but it depends on when and how often samples are taken. A measured maximum can miss a true peak if sampling does not occur near it. The registry record gives the outcome unit as ng/mL and the timeframe as four procedure days for each participant, but the detailed sampling schedule and actual measurements are not reported.

The primary outcome is characterized as a mean with standard deviation. In general, the mean is a measure of the center of numerical observations, while the standard deviation describes their spread. Both would help readers understand the scale and variability of Cmax. The registry record does not report their numerical values, so no quantitative statement about the average or dispersion can be made.

What does a crossover design contribute?

In general, a crossover study measures the same participants under different conditions. A within-person comparison can reduce the influence of stable person-level characteristics, because each participant serves as their own reference. This benefit depends on how the treatment sequence and time effects are handled. The registry describes Nicoderm procedures first and Aveva procedures afterward, with no random allocation. It does not report a model or analysis that accounts for period, sequence, or within-person correlation.

When repeated measurements from a participant are analyzed, those observations may be correlated rather than independent. General methods for repeated or paired data account for that dependence. Treating correlated measurements as independent can misstate uncertainty. The registry lists zero analyses and does not describe whether a paired analysis, repeated-measures model, or another method was planned or used. It is therefore not possible to say which approach generated a treatment comparison.

A fixed order also makes it difficult to distinguish a condition effect from a period effect. In general, period effects include changes associated with time or study sequence rather than the patch itself. A randomized sequence can help balance such effects across conditions, while a fixed sequence cannot do so in the same way. The record does not report an analysis addressing this issue, and it does not describe a washout interval. No assumptions about washout or carryover can be made from the information recorded.

How should uncertainty be read?

In general, a confidence interval gives a range of values compatible with the data and the assumptions of the statistical method. Its width conveys precision: a wider interval indicates greater uncertainty about the estimated effect, while a narrower interval indicates greater precision. A confidence interval does not show the probability that a particular fixed value is true. No confidence interval for Cmax or AUC is reported in the registry record.

A p-value, in general, describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the statistical model were true. It does not measure the size or clinical importance of an effect. The registry does not report a p-value or a hypothesis test for the primary outcome. In the absence of an estimate, interval, and test result, statistical significance cannot be assessed. More importantly, statistical significance alone would not establish bioequivalence; that question requires a stated equivalence criterion and an estimate with uncertainty evaluated against it.

What do the safety counts show statistically?

The adverse-event entries give the number at risk and the number affected in each recorded condition. These are descriptive counts. General comparisons of event frequency need to account for the study structure, the number of participants, and whether an individual can contribute events under more than one condition. With the same participants appearing across conditions, separate rows do not represent independent groups. No comparative safety model or uncertainty estimate is reported.

The serious adverse event counts are zero in every condition. A zero count describes what was recorded in this sample; in general, it does not prove that an event cannot occur. The sample is small, and the record provides no comparative safety analysis. The numbers should therefore be read as a report of observed counts rather than as a precise estimate of risk or as evidence of equivalence in safety.

What can the planning illustration establish?

The record describes a sample-size planning illustration based on a fraction of the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the illustration is not the trial's own design calculation. Such an illustration is a hypothetical planning exercise, not an observed study result and not observed power. It cannot establish how the original trial was designed or whether the original sample size was justified.

The statistical plan, original sample-size justification, and numerical planning outputs are not reported in the registry record. Because numerical Cmax estimates are also absent, the observed effect used for the illustration cannot be evaluated from the record. Any planning count should be understood as a scenario under stated assumptions, not as a claim about the study's ability to detect an effect after completion.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists Cmax as the primary outcome and AUC as a secondary outcome. It also records two outcome measures and zero analyses. It does not report a multiplicity plan describing how to handle the possibility of testing more than one outcome or comparison. In general, when several statistical tests are conducted, the chance of at least one apparently unusual result can increase. Prespecified priorities or adjustment methods can address this issue, but no such method is reported.

The registry record does not provide numerical results for Cmax or AUC, and it reports no inferential analyses. It does not state whether any outcomes were omitted, changed, or analyzed in multiple ways. A statistical analysis plan and a prespecified hierarchy of outcomes are not reported in the registry record, so it is not possible to determine how outcome selection or multiplicity was handled.

The record states that ten participants completed the study. It does not describe missing measurements, exclusions from an analysis, or methods for handling incomplete data. In general, missing data can affect estimates if the availability of measurements is related to the outcome or condition. Common approaches include analyzing observed measurements under stated assumptions or using a model designed for incomplete repeated data; the appropriate method depends on the design and reasons for missingness. No such approach is reported.

The analysis population is not defined beyond the statement that ten adult smokers completed the study. The registry does not specify whether all completed measurements were included in each outcome analysis or whether any participant-level exclusions occurred. These details are necessary to connect the enrolled and completed sample with the population contributing to an estimate.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

For serious adverse events, the registry lists zero affected participants among ten at risk in each of four conditions: Nicoderm Patch 4 h Heat Application, Nicoderm Patch 8 h Heat Application, Aveva Patch 4 h Heat Application, and Aveva Patch 8 h Heat Application. It also lists zero deaths in each condition. These entries describe what was recorded during the study; they do not establish that the risk of a serious event is zero.

The registry separately records other adverse events in each condition. The counts affected are 5 of 10 for Nicoderm Patch 4 h Heat Application, 6 of 10 for Nicoderm Patch 8 h Heat Application, 7 of 10 for Aveva Patch 4 h Heat Application, and 4 of 10 for Aveva Patch 8 h Heat Application. The record does not provide event terms for these entries in the listed serious-event terms field, nor does it give an analysis comparing conditions.

Because the same ten participants underwent multiple conditions, these condition-specific counts may include the same participants in more than one condition. They should not be summed to infer the number of distinct people who experienced an event. The counts also do not give event severity, timing, duration, or a statistical uncertainty estimate. They are descriptive safety information from a small completed study, not a comparative conclusion.

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

The record describes a small crossover study that measured maximum serum nicotine concentration during use of a reference patch and a generic patch, with heat applied at specified times. It also records adverse-event counts for four patch-and-heat conditions. These details clarify the intended comparison and the procedures participants completed.

The record does not report the numerical Cmax results or a statistical comparison between the patches. It therefore cannot show whether average peak serum nicotine concentrations differed, how large any difference was, or how precisely it was estimated. The listed AUC outcome likewise has no numerical result. Although the study is described as a bioequivalence study, the record does not report an equivalence margin or analysis, so it does not establish whether a bioequivalence criterion was met.

The fixed order is another important qualification. Participants used Nicoderm before Aveva, and the study was not randomized. A difference between periods, if one existed, could be entangled with the patch comparison. The registry does not report an analysis that addresses this issue. The design description alone does not resolve it.

The safety counts show no recorded serious adverse events or deaths in the listed conditions, alongside recorded other adverse events. These observations describe this study sample and should not be generalized as proof that serious events cannot occur or that safety is the same between conditions. No comparative safety analysis is reported.

In general, a result that is not reported cannot be interpreted as either a positive finding, a negative finding, or evidence of no difference. The scientifically supportable reading is limited to the design, endpoint definitions, completion count, and descriptive safety data recorded in the registry. Claims about the magnitude, precision, or direction of nicotine exposure differences require results that are not reported in the registry record.

13. Why This Trial Matters Statistically

This study raises several statistical issues that are useful to recognize when reading pharmacokinetic and crossover research. First, a crossover design can use within-participant measurements, which may make comparisons more informative than comparisons between unrelated groups when stable participant characteristics influence the outcome. That advantage depends on suitable sequencing and analysis. Here, the registry describes the same order for all participants and does not report the statistical method used to account for repeated measurements.

Second, a bioequivalence question requires more than measuring an endpoint in two conditions. General bioequivalence assessment relies on a defined comparison, a prespecified margin, and uncertainty around the estimated difference or ratio. The registry record does not report a margin, comparison estimate, or confidence interval. The study title and stated purpose are not evidence that a criterion was satisfied.

Third, peak concentration and total exposure are different summaries. Cmax captures a peak, while AUC summarizes concentration over time. Considering both can provide complementary information, but the registry gives no numerical results for either outcome. This illustrates why endpoint names alone are insufficient to interpret findings: estimates, variability, and analysis details are needed.

Finally, the distinction between a completed study and a reported analysis matters. Ten participants completed the study, but the registry lists zero analyses and gives no numerical primary outcome results. Completion establishes that the study reached its recorded status, not that readers can evaluate the statistical evidence. The record is therefore useful for understanding the study's design and the limits of the available evidence, but it does not support a quantitative conclusion about the patch comparison.

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 registry record has important study-specific limitations for statistical interpretation. The most immediate is that it defines Cmax as the primary endpoint but does not report its numerical values. It also does not report the numerical AUC results. Without those outcome estimates, readers cannot assess direction, magnitude, variability, or precision.

The study is described as nonrandomized and single-group, with Nicoderm always preceding Aveva. In general, a fixed sequence can confound patch condition with period or order. The record does not describe a washout interval or a model accounting for sequence, period, repeated measurements, or possible carryover. These features are not evidence that such effects occurred, but the registry does not provide information to assess them.

The participant group was ten adult smokers between 24 and 44 years of age. The record does not provide additional sample characteristics or explain how participants were selected. The size and composition of this group limit the scope of any inference, and the absent efficacy estimates make even a within-study quantitative assessment impossible.

Key analysis details are not reported: the statistical model, the analysis population, missing-data handling, multiplicity approach, and prespecified criteria for bioequivalence. The record also does not report the original sample-size justification. The planning illustration is described as distinct from the trial's design calculation, and its numerical outputs are not included in the registry record.

Finally, the safety information is descriptive, with no comparative analysis or uncertainty estimates. Because the same participants experienced multiple conditions, counts across condition rows cannot be assumed to represent distinct individuals. These limitations mean that the record supports a careful description of the procedures and recorded counts, but not a complete statistical evaluation of efficacy, equivalence, or comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Transdermal Patch CVD 1000: The Effect of Heat on Nicotine Release From Nicotine Patches in Adult Smokers — NCT02371850.
• Registry record last updated 2021-06-16; status last verified 2021-06.
• Results first posted 2017-08-17.
• 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

NCT02371850 is a completed Phase 4, single-group, open-label, nonrandomized crossover study sponsored by the University of Maryland, Baltimore. Ten adult smokers between 24 and 44 years of age completed four procedure days. The recorded sequence used the Nicoderm CQ reference patch first and the Aveva generic patch afterward, with one-hour heat applications at hours 4 and 8 after application.

The primary outcome was mean maximum serum concentration, Cmax, in ng/mL, over the four procedure days for each participant. AUC was listed as a secondary outcome. Numerical efficacy results and analyses are not reported in the registry record. Serious adverse events and deaths were recorded as zero in each of the four conditions; other adverse-event counts were recorded for each condition. The fixed sequence and absence of reported outcome estimates constrain interpretation of the patch comparison.