Pharmacokinetics & Tolerability Study of MAP0004 in Smoking and Non-Smoking Adult Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics & Tolerability Study of MAP0004 in Smoking and Non-Smoking Adult Volunteers (NCT01199965), a randomized phase 1, phase 2 study. The primary outcome is Cmax of Dihydroergotamine After MAP0004 and IV DHE Administration in Smokers Versus Non-smokers.

2. Clinical Question

The question has two connected parts: whether the measured concentration profile differs across treatment and smoking-status groups, and whether tolerability observations differ between smokers and non-smokers receiving MAP0004. The primary endpoint is Cmax, the highest measured plasma concentration during the specified observation period. The registry gives a geometric mean for each treatment-by-smoking-status group, with a standard deviation as the reported spread.

The posted results are descriptive group values. The registry record does not report a formal estimate of the treatment contrast, a smoking-status contrast, or an interaction between treatment and smoking status. It also does not report a statistical test establishing whether any observed group pattern is distinguishable from sampling variability. Accordingly, the values can be read as the recorded concentrations in the analyzed groups, but they do not alone settle the comparative question.

3. Trial Design

This was a randomized, open-label, two-period crossover study listed as Phase 1 and Phase 2. It enrolled 47 healthy adult volunteers and was completed. The registry records a start date of 2010-01 and primary completion in 2010-04. The sponsor was Allergan.

Each participant was assigned to one of two treatment orders: IV DHE followed by MAP0004, or MAP0004 followed by IV DHE. The second treatment was given 7-11 days after the first. Both smokers and non-smokers were included in the treatment sequences. Because the design is crossover, participants received both treatments; the sequence labels describe order rather than separate groups of people who received only one treatment.

Open-label means masking was not used. The registry record does not report additional details about how randomization was generated or concealed, or whether any procedures were used to limit measurement or assessment bias. It also does not report the rationale for the interval between treatment visits or further protocol details about period effects.

The primary endpoint is the geometric mean Cmax within each treatment and smoking-status group. The posted endpoint counts are 22 for smokers and 24 for non-smokers for each treatment. These counts describe available endpoint data, not the enrollment total. Safety counts use their own at-risk groups, so those counts should not be assumed to match the endpoint analysis counts.

The registry lists two outcome measures and no posted analyses. It does not report a sample-size justification, a prespecified inferential analysis plan, or whether any interim analyses were planned. Those details 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.

Before assignment: All smoking and non-smoking subjects received both MAP0004 and Intravenous (IV) Dihydroergotamine (DHE).

Overall Study

Analysis population for the primary outcome, as defined in the registry: Patients with available data at specified time points are included in the analysis population.

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 Cmax of Dihydroergotamine After MAP0004 and IV DHE Administration in Smokers Versus Non-smokers, measured over 48 hours.

The primary endpoint is the maximum concentration, or Cmax, of dihydroergotamine measured in plasma after MAP0004 or IV DHE administration. Plasma is the clear portion of blood, and the concentration unit is pg/ml. The endpoint timeframe is 48 hours. The registry describes the analysis population as participants with available data at specified time points.

Cmax captures the highest measured concentration during the observation period. In pharmacokinetic research, it is one way to describe the concentration reached after a dose; it does not by itself describe the full concentration-time profile, total drug exposure, duration of exposure, or a clinical outcome. General explanation: concentration values over time can answer different questions, so one peak measure cannot stand in for every aspect of pharmacokinetics.

The registry reports geometric means and standard deviations for the four treatment-by-smoking-status groups. The geometric mean is a measure of central tendency often used for positive, potentially skewed concentration data. A standard deviation describes dispersion around a mean on its applicable scale; the registry does not clarify how the listed standard deviations were derived alongside the geometric means. The record does not provide confidence intervals for these endpoint values.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General: A crossover study gives each participant more than one treatment in a planned order. The participant can serve as their own reference because outcomes under the different treatments come from the same person. This can account for stable differences between participants, but it requires appropriate analysis of within-participant data and attention to treatment order and period. The registry identifies this study as a randomized crossover with two periods, but does not report the statistical method used to analyze the crossover data.

The recorded sequences were IV DHE followed by MAP0004 and MAP0004 followed by IV DHE, with the later treatment given 7-11 days after the first. General: Randomizing sequence can help balance order effects across treatment orders. It does not, on its own, demonstrate that carryover or period effects were assessed. The registry record does not report whether those effects were tested, modeled, or otherwise addressed.

The primary measure is Cmax, summarized as a geometric mean and standard deviation for each of four groups. General: Geometric summaries are commonly used for positive measurements that may be skewed, because values can span a wide range. The geometric mean is not the same as the arithmetic average. The record does not specify a transformation or other calculation details behind the summaries, so no additional distributional assumptions can be attributed to the analysis.

A standard deviation describes the spread of observations, while a confidence interval describes uncertainty in an estimated quantity. These are different kinds of information. The registry labels the reported spread as standard deviation but does not provide confidence intervals for Cmax. It also does not clarify whether the standard deviations are on the original measurement scale or another scale. Therefore, the posted summaries do not quantify the precision of a treatment contrast or smoking-status contrast.

The registry reports zero analyses. It consequently offers no posted model estimate or test for the primary endpoint. No treatment difference, smoking-status difference, or treatment-by-smoking-status interaction is reported. General: A factorial comparison of treatment and smoking status could distinguish an overall treatment pattern from a difference in treatment response across smoking groups, but the registry does not report such an analysis. No result of that kind should be inferred from the four separate group summaries.

Sample-size planning and observed precision answer different questions. The registry’s planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Any sample-size values based on such assumptions are planning illustrations, not observed power and not evidence that the study had a particular probability of detecting an effect. The record does not report the trial’s own sample-size justification, and no sample-size calculation should be treated as the study’s design rationale.

General: Over-dispersion occurs when observed variability is greater than a model assumes. If present, it can make standard errors too small and confidence intervals too narrow under an unsuitable model. The registry does not report a model for the endpoint, a dispersion assessment, or model diagnostics; over-dispersion therefore cannot be assessed from the posted record.

For safety, the registry provides counts of participants at risk and counts affected by serious or other adverse events for each exposure group. These are descriptive summaries, not modeled risks or comparative estimates. General: A formal comparison would need to account for the crossover structure and the fact that the same participant may contribute information under both treatments. The record does not report such a method. It also does not report statistical methods for missing observations, multiplicity, or sensitivity analyses.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures but no posted analyses. It does not report how many statistical hypotheses were planned, whether the outcomes were ordered in a testing hierarchy, or whether any adjustment for multiple comparisons was specified. A multiplicity strategy is therefore not reported in the registry record. Without a posted inferential analysis, there is no documented family of tests or adjusted significance threshold to interpret.

The primary endpoint population is described as participants with available data at specified time points. The record does not report how many observations were missing, why data might be missing, or how missing endpoint values were handled. It does not state whether the analysis followed an intention-to-treat principle, a per-protocol approach, or another prespecified population definition. The endpoint counts are reported by group, but they do not explain the handling of incomplete measurements.

The enrollment total is 47, while the listed endpoint counts are 22 for smokers and 24 for non-smokers within each treatment group. The registry does not explain the relationship between all enrolled participants and the available endpoint data. It also does not report whether participants who discontinued or lacked measurements were included in any other analysis population.

For adverse events, the at-risk counts are given separately by treatment and smoking status. The record does not report a method for accounting for repeated exposure within participants, nor does it provide a missing-safety-data explanation. These omissions limit how far descriptive counts can be compared. No assumptions about missingness, analysis populations, multiplicity control, or sensitivity analyses should be inferred from the record.

11. Safety Results

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

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 lists zero serious adverse events in each of the four treatment-by-smoking-status groups. The at-risk counts are 23 for smokers receiving MAP0004, 24 for non-smokers receiving MAP0004, 22 for smokers receiving IV DHE, and 24 for non-smokers receiving IV DHE. No serious adverse-event terms are listed. Death counts are not reported in the registry record.

Other adverse events affected 4 participants in the MAP0004 smoker group, 8 in the MAP0004 non-smoker group, 15 in the IV DHE smoker group, and 22 in the IV DHE non-smoker group. These are participant counts, not severity-adjusted measures or statistical comparisons. No causal attribution or comparative test is posted.

Because participants received both treatments in a crossover, the treatment-specific safety groups are exposure summaries, not independent sets of people assigned to receive only one treatment. The listed at-risk counts also differ from some endpoint counts. The registry does not explain these differences or report inferential safety analyses, so the counts are best read as descriptive reporting within the stated exposure groups.

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

The results establish what the registry reports: geometric mean Cmax values for four combinations of treatment and smoking status, along with standard deviations and available-data counts. They also provide descriptive adverse-event counts by exposure group. These observations may help characterize the recorded pharmacokinetic and tolerability data in this study population.

They do not establish whether the treatments differ statistically, whether smokers and non-smokers respond differently, or whether an apparent pattern is precise enough to distinguish from chance variation. The registry does not provide confidence intervals, p-values, or formal estimates for those questions. No conclusion about a clinically meaningful difference can be drawn from group summaries alone, particularly because no clinical threshold is reported.

The results also do not describe every aspect of exposure. Cmax is a peak concentration measure over the stated 48 hours, not a complete concentration-time analysis or a measure of total exposure. Nor does this endpoint itself establish a clinical benefit or harm. The study population is described as healthy adult volunteers, so the posted results should be understood in that population rather than generalized to an unreported population.

The absence of serious adverse events in the listed groups is a descriptive finding for the recorded at-risk groups. It does not prove that serious events cannot occur, and the registry does not provide a statistical safety comparison. Similarly, the other-event counts do not establish that one treatment is safer or less safe than another.

Overall, the registry offers group-level descriptive evidence but does not post the inferential analyses needed to resolve the comparative questions. Interpretation should remain limited to the recorded measurements, counts, and design details.

13. Why This Trial Matters Statistically

This study illustrates why design and analysis details matter when interpreting pharmacokinetic data. A crossover design exposes participants to both treatments, which can support within-person comparisons. At the same time, conclusions depend on how treatment order, period, and any carryover are handled. The registry identifies the crossover structure and treatment sequences, but does not report the analysis of those features.

Separating treatment from smoking status is also important. The primary endpoint is reported in four groups, permitting descriptive inspection of both dimensions. But separate group means are not a substitute for an explicit estimate of treatment contrast or an analysis of whether treatment patterns differ by smoking status. Those results are not reported in the registry record.

The study also demonstrates the distinction between central tendency, variability, and precision. Geometric means describe group concentration levels, standard deviations describe spread, and confidence intervals would describe uncertainty in estimated values or contrasts. The registry provides the first two but not confidence intervals or inferential tests. Readers should not treat visible differences between summary values as conclusive evidence of a population-level effect.

Finally, the endpoint and safety summaries answer different questions. Cmax characterizes a peak plasma concentration, while adverse-event counts describe reported safety observations. Neither alone supplies a full account of pharmacokinetics or a comparative safety analysis. The record’s omissions make transparent reporting of analysis populations, missing data, and statistical methods particularly relevant to understanding what can and cannot be concluded.

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.

Several trial-specific limitations are apparent from the registry record. It reports no analyses, so the primary endpoint has no posted inferential comparison, confidence interval, or p-value. The group-level geometric means and standard deviations do not reveal the within-participant treatment contrasts that are central to interpreting a crossover study.

The record does not explain how the randomized sequence was generated or concealed, or how the analysis addressed treatment order, period, or possible carryover. The washout interval is recorded as 7-11 days, but the rationale for that interval and any assessment of its adequacy are not reported in the registry record. Masking was absent, and the record does not describe measures to reduce bias in measurement or assessment.

The endpoint population is defined by data availability at specified time points, but missing-data counts, reasons, and handling are not reported. The relationship between enrollment and the endpoint counts is also not explained. The record does not state a sample-size justification or provide details of a prespecified statistical plan.

Safety reporting is descriptive. Serious events are listed as zero, but deaths are not reported, and the record provides no inferential comparison or explanation of the difference between safety and endpoint counts. The study involved healthy adult volunteers, and the registry does not provide results for other populations. These limits constrain interpretation of both the pharmacokinetic summaries and the adverse-event counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics & Tolerability Study of MAP0004 in Smoking and Non-Smoking Adult Volunteers — NCT01199965.
• Registry record last updated 2014-01-09; status last verified 2013-12.
• Results first posted 2013-10-22.
• 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

NCT01199965 is a completed randomized, open-label, two-period crossover study listed as Phase 1 and Phase 2. It enrolled 47 healthy adult volunteers and compared MAP0004 oral inhalation with intravenous DHE in smokers and non-smokers. Participants received the treatments in one of two orders, with the second treatment given 7-11 days later.

The primary endpoint was dihydroergotamine Cmax in plasma over 48 hours, reported as geometric means and standard deviations. The registry lists endpoint counts and values for each treatment-by-smoking-status group, and descriptive adverse-event counts. It reports no analyses, confidence intervals, or p-values. Missing-data handling, multiplicity procedures, the sample-size justification, and further details of the statistical plan are not reported in the registry record.