Pharmacokinetics & Tolerability Study of MAP0004 Co-administered With Ketoconazole: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics & Tolerability Study of MAP0004 Co-administered With Ketoconazole (NCT01468558), a non-randomized phase 1 study. The primary outcome is Cmax of Dihydroergotamine After MAP0004, MAP0004 Co-administered With Ketoconazole, and IV DHE Administration.

2. Clinical Question

In practical terms, the pharmacokinetic question concerns how the measured peak plasma concentration differs across the treatment conditions. The ketoconazole condition is relevant to the stated comparison because it evaluates MAP0004 during co-administration with that drug. The IV DHE condition provides a reference treatment for interpreting the inhaled regimen. These are study questions, not evidence by themselves that one treatment condition produced greater or lesser exposure.

The tolerability question is distinct from the Cmax question. Safety counts describe adverse events recorded in each treatment condition, but they do not establish comparative pharmacokinetic effects. The registry record contains serious-event and other-adverse-event counts; detailed event terms and a complete account of tolerability outcomes are not reported in the registry record.

3. Trial Design

This was a completed Phase I study with a non-randomized, single-group design and no masking. The registry record lists 24 participants and identifies the population as healthy. Because allocation was non-randomized, the treatment conditions should not be read as randomized parallel groups or as a like-for-like control comparison. The record describes a sequence in which subjects received the study treatments at different visits.

At Visit 2, subjects received MAP0004 on Day 1. Ketoconazole was administered on Days 3 through 6 of that visit, and MAP0004 was administered again on Day 6. Subjects then returned for Visit 3, 7-11 days from the end of Visit 2, and received 1.0 mg IV DHE. This sequence makes clear that the registry’s pharmacokinetic question concerns multiple treatment conditions within the study. The record does not state whether every enrolled subject completed every treatment or contributed data to each endpoint.

The study began in 2010-07 and reached primary completion in 2010-08. These dates place the recorded study activity in a short period, but the registry record does not describe the duration of participant follow-up beyond the visit information given. The primary endpoint timeframe is 48 hours.

The study’s non-randomized sequence is important for interpretation. General statistical context: when treatment order is not randomized, differences between conditions can be entangled with factors such as order or period effects. A within-person sequence can reduce some sources of between-person variation when the same people contribute measurements under each condition, but a causal interpretation depends on design and analysis details. Those details, including any adjustment for order or period, are not reported in the registry record.

The registry identifies Allergan as sponsor. It does not report a detailed statistical analysis plan, a sample-size justification, or methods for handling the treatment sequence. The safety denominators also vary by condition, so the record does not support assuming that every participant contributed to every safety 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.

Before assignment: All subjects received MAP0004 on Day 1 of Visit 2, Ketoconazole on Days 3 through 6 of Visit 2, and MAP0004 again on Day 6 of Visit 2. Subjects then returned for Visit 3, 7-11 days from the end of Visit 2. At Visit 3 subjects received 1.0 mg Intravenous (IV) Dihydroergotamine Mesylate (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, MAP0004 Co-administered With Ketoconazole, and IV DHE Administration, measured over 48 hours.

The primary endpoint is Cmax, the maximum concentration of DHE measured in plasma. Plasma is the clear portion of blood, and the endpoint is expressed in pg/ml. Cmax captures the observed peak concentration within the measurement period; it is one aspect of a drug’s concentration profile and does not, by itself, describe the full profile or total exposure.

The registry record specifies a 48-hour timeframe and states that Cmax is reported as a geometric mean with standard deviation. A geometric mean summarizes measurements on a multiplicative scale and can be useful when values are positive and have a skewed distribution. General statistical context: unlike an arithmetic mean, a geometric mean reflects relative rather than additive variation. The choice can be appropriate for concentration data, although the record does not explain the rationale for the chosen summary.

The endpoint was intended to support comparisons among MAP0004, MAP0004 co-administered with ketoconazole, and IV DHE. A concentration peak can help describe how high measured plasma levels rise after a treatment, but interpretation of a difference requires the actual estimates and their uncertainty. Numerical Cmax estimates, standard deviations, confidence intervals, and comparative tests are not reported in the registry record. Consequently, the endpoint definition is available, while its observed results cannot be characterized from the registry information presented.

The analysis population is described as patients with available data at specified time points. The number of available observations at each time point, and how missing concentration measurements were handled, are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a concentration measurement rather than a clinical event outcome. Cmax denotes the highest plasma concentration measured during the stated timeframe. The record specifies measurement in pg/ml over 48 hours. This definition indicates what quantity was to be summarized, but not the sampling schedule, the number of concentration measurements, or the method used to determine the maximum when observations were unavailable or irregularly timed. Those details are not reported in the registry record.

What does a geometric mean summarize?

The registry specifies a geometric mean and standard deviation. General statistical context: a geometric mean is formed on a logarithmic scale and then expressed back on the original scale. It is often useful for positive measurements with a right-skewed distribution, as can occur with concentration data. It represents a multiplicative center rather than the ordinary arithmetic average. A geometric mean is not interchangeable with an arithmetic mean, so readers should interpret it according to the stated scale.

Standard deviation describes dispersion around a summary, but interpretation depends on the scale and method used to calculate it. The record names standard deviation without giving the observed values or further calculation details. It does not state whether dispersion was calculated on the original concentration scale or after transformation. In the absence of the estimates, neither the central exposure nor its variability can be described.

Why does uncertainty matter?

General statistical context: a point estimate describes the value estimated from observed data, while a confidence interval communicates uncertainty around that estimate under the chosen statistical model. A narrow interval indicates greater precision than a wide interval, but an interval does not remove design limitations or establish clinical importance. For a treatment comparison, the estimate and its interval are more informative than a statement that a difference was or was not statistically significant. The registry record does not report Cmax estimates, comparative estimates, confidence intervals, or p-values.

For a geometric-mean comparison, analysts may compare transformed measurements or use a ratio-scale contrast, depending on the prespecified analysis. This is general methodological context, not a description of the analysis used in this study. The registry record does not report the specific model, transformation, contrast, or adjustment method. No comparison should be reconstructed from the endpoint description alone.

What does the treatment sequence imply?

The study is described as non-randomized and single-group. Subjects received MAP0004, then ketoconazole over Days 3 through 6 with another MAP0004 administration on Day 6, followed by IV DHE at Visit 3, 7-11 days after Visit 2 ended. General statistical context: repeated treatment conditions in the same participants can allow each participant to serve as a reference for their own measurements, potentially reducing variation due to stable participant characteristics. But sequential administration can also make treatment effects difficult to separate from period, order, or carryover effects. Whether those concerns were addressed depends on protocol and analysis choices; those choices are not reported in the registry record.

The registry does not state that a washout period was used, nor does it describe the rationale for the interval between visits. It would be inappropriate to infer a washout or assume that carryover was absent. The interval between visits is reported, but its statistical purpose is not.

How should safety counts be understood?

Safety counts are descriptive event summaries, not estimates of comparative risk unless the event definitions, observation periods, participant denominators, and analysis methods are clear. General statistical context: a count alone does not convey the probability of an event without its denominator, and a difference in counts can reflect different numbers observed or different follow-up. The record lists participants at risk and affected counts for serious and other adverse events. The serious-event affected count is zero in each listed condition. Other adverse-event counts are also listed, but event details and comparative analyses are not reported in the registry record.

The IV DHE safety denominator differs from the MAP0004 denominators. That difference should be retained when reading the counts rather than treating the conditions as equal-sized groups. The reason for the difference is not reported in the registry record. Death counts are not reported in the registry record.

What can planning calculations establish?

General statistical context: a sample-size calculation can illustrate how many participants might be needed under stated assumptions to detect a specified effect with a chosen error rate and power. Such a calculation is a planning illustration, not an observed trial result and not observed power. The record describes its planning illustrations as based on the observed effect and states assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. It also states that the target effect is a stated fraction of the observed effect. The actual illustration outputs are not reported in the registry record in the registry record described for this analysis, and no design justification is reported.

Those generic assumptions do not establish that the trial was designed with those properties. In particular, the record does not report the study’s own sample-size rationale, a prespecified statistical plan, or interim analyses. No inferential method should be attributed to the study without that information.

10. Multiplicity, Missing Data and Analysis Populations

The registry record describes several pharmacokinetic treatment conditions and a tolerability objective. It does not state how many pairwise or other comparisons were prespecified, whether one contrast was designated as primary for inference, or whether any method was used to address multiplicity. The primary endpoint title names three treatment conditions, but that wording does not establish an adjustment strategy or a hierarchy of comparisons. Statistical analysis results are not reported in the registry record.

Multiplicity can arise when several outcomes, time points, treatment contrasts, or subgroups are examined. General statistical context: as the number of statistical tests increases, the chance of at least one false-positive result can increase if each test is interpreted independently. Adjustments or prespecified testing hierarchies can address this issue, but the appropriate approach depends on the study question and analysis plan. The registry record does not report whether any such approach was used.

The analysis population is described as patients with available data at specified time points. The record does not report the number contributing to each Cmax summary, the handling of missing measurements, or whether the analysis followed any defined population principle. The available-data description does not by itself establish how incomplete records were treated or whether missingness differed by treatment condition.

The safety denominators are 24 for MAP0004 1.0mg, 24 for MAP0004 1.0mg + Ketoconazole, and 22 for IV DHE 1.0mg. The reason for the smaller IV DHE denominator is not reported in the registry record. It is also not stated whether participants without data were excluded, whether exposure or follow-up differed, or how those differences affected analysis. The registry record does not report an imputation method, a sensitivity analysis, or an analysis population for safety beyond the listed at-risk counts.

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 serious adverse events and other adverse events separately for the three treatment conditions. The serious adverse-event affected count is 0 for MAP0004 1.0mg, 0 for MAP0004 1.0mg + Ketoconazole, and 0 for IV DHE 1.0mg. The corresponding numbers at risk are 24, 24, and 22. These are reported counts, not evidence that no unrecorded or unreported events occurred.

In the registry’s other-adverse-event category, the affected counts are 6 for MAP0004 1.0mg, 7 for MAP0004 1.0mg + Ketoconazole, and 11 for IV DHE 1.0mg. The listed numbers at risk are 24, 24, and 22, respectively. These descriptive counts should be read alongside their denominators; they are not a randomized comparison and do not establish a treatment-related difference.

The record does not list serious adverse-event terms. It also does not report death counts, the specific other adverse-event terms, event severity, or comparative statistical analyses. The reason the IV DHE safety denominator differs from the two MAP0004 denominators is not reported in the registry record. Consequently, these figures provide a limited count-based view of safety reporting rather than a complete assessment of tolerability.

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

The study’s stated purpose was to compare DHE pharmacokinetic profiles after MAP0004, MAP0004 co-administered with ketoconazole, and IV DHE, and to compare tolerability across those conditions. Its primary endpoint was Cmax over 48 hours. The record’s treatment schedule and endpoint definition make the scientific question clear, but the numerical Cmax findings are not reported in the registry record.

That gap means the direction, size, and precision of any exposure contrast cannot be stated. The record does not show whether peak concentrations were higher, lower, or similar across conditions. It also does not report confidence intervals or p-values that would characterize uncertainty or statistical evidence for a difference. The endpoint description alone cannot answer the pharmacokinetic question.

The safety information supports only a limited descriptive statement: no serious adverse events were recorded among those listed at risk in any of the three conditions, while other adverse events were recorded with the counts stated above. The registry record does not provide event details, deaths, or inferential safety comparisons. These counts should not be treated as proof of equivalence or as a complete characterization of tolerability.

The design further constrains interpretation. Allocation was non-randomized, masking was absent, and the treatment conditions were administered in sequence within a single-group study. General statistical context: such a design can describe measurements across treatment conditions, but separating treatment effects from sequence or time effects depends on analysis choices. Those choices are not reported in the registry record.

Accordingly, the record documents a Phase I investigation in healthy volunteers and identifies its intended pharmacokinetic and tolerability comparisons. It does not permit a conclusion about comparative exposure, a causal interaction with ketoconazole, or comparative safety. Such conclusions would require outcome estimates and analysis details that are not reported in the registry record. This interpretation concerns the information available in the registry, not a clinical recommendation.

13. Why This Trial Matters Statistically

This trial is statistically notable for asking a pharmacokinetic question across different administration conditions, including MAP0004 with and without ketoconazole and IV DHE as a reference. A maximum plasma concentration is a focused measure of peak exposure, and a geometric-mean summary is suited to describing positive measurements on a multiplicative scale. The intended comparisons are clinically and pharmacologically distinct, so their estimates would need to be interpreted in light of how each treatment was administered.

The single-group, non-randomized sequence is central to the statistical reading. When the same participants contribute measurements under multiple conditions, within-person comparisons can account for stable differences among people. At the same time, sequential treatment creates potential order and period considerations. Whether the study analysis addressed these issues is not reported in the registry record. This makes the missing analysis details especially relevant to interpreting any treatment contrast.

The record also illustrates why endpoint definitions and endpoint results must be distinguished. It specifies Cmax, units, a timeframe, and a summary measure, yet does not report the numerical pharmacokinetic findings or their uncertainty. Without those results, the main scientific comparison cannot be quantified. The safety counts offer descriptive information, but they do not substitute for a complete tolerability analysis or a comparative statistical assessment.

Finally, the available safety denominators differ for IV DHE and MAP0004 conditions. Keeping each denominator attached to its count is important; comparisons of raw counts alone can be misleading when the numbers at risk differ. The record does not explain that difference. Overall, the study’s statistical interest lies in its repeated-condition pharmacokinetic question and the limitations that arise when results and analysis methods 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.

Several limitations specific to this record affect interpretation. The primary endpoint is defined, but numerical Cmax results, dispersion estimates, comparative contrasts, confidence intervals, and p-values are not reported in the registry record. As a result, neither the size nor precision of any pharmacokinetic difference can be assessed.

The study was non-randomized, unmasked, and described as single-group. Treatment was administered in sequence, with MAP0004 before and during ketoconazole administration and IV DHE at a later visit. The record does not describe adjustment for order or period effects, nor does it report the analysis model. The sequence therefore cannot be treated as a randomized comparison.

The primary analysis population is described as patients with available data at specified time points, but the number of observations at each time point and the handling of missing data are not reported in the registry record. The record also does not establish that every enrolled subject completed or contributed data to every condition.

For safety, the IV DHE denominator is 22, compared with 24 for each MAP0004 condition. The reason for this difference is not reported in the registry record. The serious-event counts are listed, but serious event terms and death counts are not reported. Other adverse-event terms, severity, follow-up details, and comparative safety analyses are also not reported.

The registry record does not report a detailed statistical analysis plan, multiplicity procedure, sample-size justification, or interim analyses. These omissions limit assessment of whether comparisons were prespecified and how uncertainty or missing observations were handled.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics & Tolerability Study of MAP0004 Co-administered With Ketoconazole — NCT01468558.
• 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

This record describes NCT01468558, a completed Phase I study sponsored by Allergan. It enrolled 24 healthy volunteers and used a non-randomized, unmasked, single-group design. Subjects received MAP0004, MAP0004 with oral ketoconazole, and 1.0 mg IV DHE in a sequence across visits.

The primary endpoint was DHE Cmax in pg/ml over 48 hours, summarized as a geometric mean with standard deviation. The registry record does not report numerical Cmax results or comparative analyses. It lists zero serious adverse events in each treatment condition and other-adverse-event counts of 6, 7, and 11, with at-risk denominators of 24, 24, and 22, respectively. Serious-event terms and death counts are not reported in the registry record.