A Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers (NCT03303911), a randomized phase 1, phase 2 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax).

2. Clinical Question

3. Trial Design

The registry describes a randomized, unmasked, parallel-group study in healthy smokers, with 26 participants enrolled. The study is listed as Phase 1 and Phase 2. Its title and objectives identify repeat-dose pharmacokinetic and pharmacodynamic evaluation of cytisine. The registry status is terminated; the reason for termination is not reported in the registry record.

The two study groups received cytisine at 1.5 mg or 3.0 mg per dose under the same 25-day schedule. Dosing was most frequent at the beginning and tapered over time, from six times daily on Days 1-3 to once daily on Day 25. The registry does not describe a placebo group. Because masking is listed as none, participants and study personnel were not masked according to the recorded design.

The stated primary objectives were to evaluate pharmacokinetic parameters during repeat dosing and pharmacodynamic effects, including reduction in smoking. The registered primary outcome was Cmax, assessed after the first dose and the last dose on Day 1, after the last dose on Days 2, 3, 12, 16, 20, and 24, and after the morning dose on Day 25. Secondary outcomes included urinary excretion measures and safety assessments involving adverse events, laboratory values, vital signs, physical examinations, and electrocardiograms.

The registry lists 25 outcome measures and zero analyses. It does not report the statistical analysis plan, a sample-size justification, interim analyses, or numerical results for the primary endpoint. The listed enrollment should therefore be read as the study's reported enrollment, not as evidence that a particular statistical precision or power target was achieved.

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: Pharmacokinetic (PK) Set: All randomized participants who completed all cytisine dosing on Days 1-3, completed \>90% cytisine dosing on Days 4-25 and complied with protocol-specified criteria. Participants with an assessment at given timepoint.

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 Maximum Observed Plasma Concentration (Cmax), measured over after the first dose and the last dose on Day 1; after the last dose on Days 2, 3, 12, 16, 20, 24; and after the morning dose on Day 25.

The primary endpoint is maximum observed plasma concentration, abbreviated Cmax, measured in ng/mL. It describes the highest measured concentration of cytisine in plasma over the relevant sampling period. Pharmacokinetic studies use concentration measurements to characterize drug exposure over time; Cmax is one part of that description and does not, by itself, describe every feature of exposure.

The registry reports Cmax using a geometric mean and a geometric coefficient of variation. A geometric mean is a summary suited to positive measurements that may vary multiplicatively or have a right-skewed distribution. The geometric coefficient of variation describes relative spread around that geometric summary. These are descriptive summaries; they do not by themselves establish whether dose groups differ statistically.

Measurements were scheduled after the first dose and the last dose on Day 1, after the last dose on Days 2, 3, 12, 16, 20, and 24, and after the morning dose on Day 25. This timing can describe concentrations at different stages of the tapering schedule and during repeat dosing. The registry record does not report the numerical Cmax values, their variability, or a dose-group comparison. It also does not report a primary pharmacodynamic result. Consequently, the endpoint definition is available, but the magnitude and precision of observed Cmax results cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies Cmax as the primary outcome and specifies a geometric mean with geometric coefficient of variation as its summary approach. These summaries describe the concentration measurements, but the registry record does not report the underlying values or any inferential analysis. The distinction matters: a summary statistic describes the observed data, while an inferential analysis would quantify uncertainty or evaluate a specified comparison. No confidence interval or dose-group test is reported.

What does a geometric mean summarize?

General statistical explanation: measurements such as concentrations are positive and can vary in a multiplicative pattern. A geometric mean summarizes values on a logarithmic scale and then expresses the summary on the original scale. It can be useful when the distribution is skewed and relative changes are more natural to describe than additive changes. It is not the same as an arithmetic average. The geometric coefficient of variation is a measure of relative variability, rather than a measure of uncertainty in the estimated mean. The registry lists this dispersion measure but does not give its observed value.

What does Cmax capture?

General statistical explanation: Cmax is the highest concentration observed among the scheduled measurements for the relevant dosing period. Its value depends on the sampling schedule as well as the concentration profile. A measured maximum is not necessarily the true concentration peak if the peak occurs between sampling times. This general point does not establish that sampling missed a peak in this study; the registry does not report enough concentration data to assess that. Cmax also does not summarize the full concentration-time profile or directly measure a pharmacodynamic outcome such as smoking reduction.

What can be inferred from the design?

Random allocation is intended to reduce systematic differences between groups at the point of assignment. A parallel-group design assigns participants to a group that receives its assigned schedule, rather than having the same participants cross between schedules. The registry records randomization, parallel assignment, and no masking. It does not give allocation details or describe procedures used to maintain allocation concealment. With no masking, knowledge of assignment may be relevant to the conduct or assessment of outcomes, particularly outcomes involving participant behavior; the registry record does not report whether or how such effects were addressed.

The endpoint population is defined as randomized participants who completed all dosing on Days 1-3, completed >90% of dosing on Days 4-25, met protocol-specified criteria, and had a measurement at the relevant timepoint. This is a restricted pharmacokinetic analysis population, rather than an explicit statement that all randomized participants were included in every analysis. The registry does not report how many participants met these criteria or how missing measurements were handled.

What is not reported about inference?

The registry lists zero analyses. It does not report a model, hypothesis test, confidence interval method, covariate adjustment, handling of repeated measurements, or a prespecified primary dose comparison. It would be inappropriate to infer any of these methods from the endpoint definition alone. Likewise, the record does not describe interim analyses or specify how the analysis accounted for the multiple measurement occasions.

General statistical explanation: a confidence interval gives a range of values compatible with the data and the assumptions of the analysis, and can communicate precision as well as direction. A p-value, when used, evaluates compatibility with a specified null hypothesis under an analysis model; it is not a measure of effect size. Neither can be reconstructed from the endpoint label or group sizes without the relevant outcome data and analysis details. No such result is reported for Cmax in the registry record.

How should the planning illustration be read?

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It specifies that the effect to detect is a stated fraction of the observed effect. Such a calculation is a planning exercise, not observed power and not a report of the trial's actual design justification. The registry does not report the numerical planning outputs or the underlying observed effect in the trial details. The illustration therefore cannot be evaluated quantitatively, and it should not be presented as evidence that the trial was adequately powered. The record also does not state that its own sample-size decision used these assumptions.

For event-based planning, the record says time-to-event illustrations use the total number of events, while other illustrations use participants per arm. That distinction concerns the interpretation of a planning calculation, not an observed trial outcome. The registry does not report an analysis based on time-to-event data.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome was assessed at multiple scheduled occasions: after the first dose and the last dose on Day 1, after the last dose on Days 2, 3, 12, 16, 20, and 24, and after the morning dose on Day 25. The registry record does not identify a single timepoint as the primary comparison or explain how results across these occasions were intended to be combined. It also does not report a multiplicity adjustment or another strategy for interpreting repeated tests. Without an analysis plan and results, it is not possible to determine how the family of measurements was handled.

The record lists 25 outcome measures, including pharmacokinetic, urinary excretion, and safety measures, and zero analyses. It does not say which outcomes were considered confirmatory, how the primary and secondary outcomes were prioritized, or whether statistical testing was planned for each. This absence does not prove that no analysis was conducted; it means that analysis details are not reported in the registry record.

Missing-data procedures are also not reported. The pharmacokinetic analysis population requires a measurement at the relevant timepoint and adherence to specified dosing criteria, but the record does not state how many participants were excluded from that population, whether missing values were imputed, or how incomplete follow-up was treated. The reported overall enrollment does not resolve those questions.

The registry provides no statistical analysis plan, interim analysis information, or sample-size justification. It is therefore not possible to assess whether outcome selection, repeated measurements, missing data, or stopping decisions were addressed through prespecified methods. These are limitations of the record's statistical detail, not evidence that a particular method was or was not used.

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 the Cytisine 1.5 mg group, the registry reports 13 participants at risk for serious events, with zero affected, and 13 at risk for other events, with 9 affected. For the Cytisine 3.0 mg group, it reports the same counts: 13 at risk for serious events, zero affected, and 13 at risk for other events, with 9 affected. No deaths are reported in either group.

These figures are participant counts, not event totals or rates. They do not show how many events an affected participant experienced, when events occurred, how long participants were observed, or the event terms for the other events. The registry lists no serious-event terms. The counts alone do not establish that the two dose groups had equivalent safety, and they do not support a comparative risk estimate. They describe only the safety information recorded in the registry record.

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

The registry record documents a randomized, unmasked, parallel-group evaluation of cytisine at 1.5 mg and 3.0 mg per dose, using the same tapering 25-day schedule. It identifies Cmax as the primary endpoint and describes the timepoints at which pharmacokinetic measurements were planned. The study also had a pharmacodynamic objective concerning effects such as reduction in smoking.

Those design details do not reveal the observed Cmax values, their variability, or the difference between dose groups. No numerical pharmacodynamic result is reported either. As a result, the record does not show the magnitude or precision of the measured pharmacokinetic or pharmacodynamic effects. It cannot be used to determine whether either dose produced a particular outcome or whether the groups differed.

The safety counts indicate that no serious events or deaths were recorded among the participants at risk in either dose group, while 9 participants in each group were recorded as affected by other events. These counts do not describe event severity beyond the registry categories, event timing, or comparative statistical uncertainty. They should not be treated as a complete safety profile.

The registry status is terminated, but the reason is not reported. The record also does not provide a statistical analysis plan, missing-data procedures, sample-size justification, or interim analysis details. Those absences limit what can be concluded from the registry entry. The results should not be inferred from study objectives, dosing schedules, enrollment, or status alone.

13. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a clearly specified measurement plan and the absence of posted outcome estimates. Cmax is identified as the primary endpoint, the summary scale is described, and measurement occasions are listed across the dosing schedule. Those details indicate what investigators intended to characterize. They do not supply the observed concentrations or the precision of any dose comparison.

Repeated measurements create an analysis question: results across occasions might be reported separately or combined through a model, but the registry does not state which approach was used. Multiple outcome measures also raise questions about prioritization and multiplicity. With zero analyses listed, the record cannot show how those issues were handled. This illustrates why endpoint definitions and analysis methods are both important when assessing clinical evidence.

The pharmacokinetic population definition also matters. It requires completion of specified dosing and a measurement at the relevant timepoint, so it does not automatically establish that every randomized participant contributed to every endpoint assessment. The number meeting the criteria and the handling of missing measurements are not reported.

Finally, planning illustrations should not be confused with observed results or with a documented rationale for trial size. The registry describes assumptions for a planning calculation, but does not report its numerical outputs or the trial's own sample-size justification. Taken together, the record supports a careful reading of the design and reported safety counts, while leaving the central outcome estimates and their statistical uncertainty 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 registry record does not report numerical results for the primary Cmax endpoint, including geometric means or geometric coefficients of variation. It also does not report a dose-group comparison, confidence intervals, test statistics, or numerical results for the pharmacodynamic objective. This prevents assessment of the direction, size, and precision of the main outcomes.

Although the record identifies several measurement occasions and 25 outcome measures, it lists zero analyses. The statistical model, handling of repeated measurements, multiplicity approach, and distinction between confirmatory and exploratory outcomes are not reported. Missing-data handling and the number of participants in the defined pharmacokinetic analysis population are also not reported.

The registry identifies a randomized, unmasked, parallel-group design, but does not describe allocation concealment or procedures to address potential effects of knowing treatment assignment. The study enrolled 26 participants, and the safety counts are reported for 13 participants at risk in each group. These counts do not provide detailed event descriptions, follow-up duration, or comparative uncertainty.

The record's status is terminated, but the reason is not reported. It does not establish whether termination affected outcome collection or follow-up. A sample-size justification, actual statistical analysis plan, and interim analysis details are not reported. The planning assumptions described in the registry cannot fill these gaps or be treated as evidence about the results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers — NCT03303911.
• Registry record last updated 2019-10-21; status last verified 2019-10.
• Results first posted 2019-10-21.
• 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 NCT03303911, titled “A Pharmacokinetic and Pharmacodynamic Evaluation of Cytisine in Healthy Smokers.” It lists Phase 1 and Phase 2, randomized allocation, no masking, a parallel-group model, enrollment of 26, and terminated status. The study compared 1.5 mg and 3.0 mg cytisine under a 25-day tapering schedule.

The primary outcome was Cmax, summarized as a geometric mean with geometric coefficient of variation at specified dosing occasions. Secondary outcomes included urinary excretion, adverse events, laboratory assessments, vital signs, physical examinations, and electrocardiogram measures. The record lists 25 outcome measures and zero analyses. It reports no numerical primary or pharmacodynamic results. Safety counts show zero participants with serious events and zero deaths in either group, with 9 participants affected by other events in each group. The reason for termination and the statistical analysis plan are not reported in the registry record.