This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study to Evaluate Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Participants (NCT01929876), a na phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01929876 |
| Phase | Phase 1 |
| Condition | Healthy Participants |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 16 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Genentech, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Healthy participants. The registry record reports enrollment of 16 participants. The pharmacokinetic population was defined as participants who received at least 1 dose of cobimetinib and had evaluable pharmacokinetic data; its size is not reported in the registry record.
Intervention
Cobimetinib administered with itraconazole during a study that the record describes as involving multiple repeating doses. The study was open-label and used a fixed sequence across 2 periods.
Comparator
Cobimetinib without itraconazole. The primary outcome is framed as a comparison of cobimetinib maximum observed plasma concentration with and without itraconazole. The record does not report the order of the treatment conditions in the periods.
Primary question
How did co-administration of itraconazole affect cobimetinib maximum observed plasma concentration in healthy participants? The registry record names this pharmacokinetic measure as the primary outcome but does not report its numerical results.
This is a pharmacokinetic drug-interaction question, not a question about treatment of a disease. The study concerns concentrations of cobimetinib in plasma under two exposure conditions. Its primary endpoint is maximum observed plasma concentration, abbreviated Cmax. The stated units are nanograms per milliliter (ng/mL), and the planned summary is a geometric mean with geometric coefficient of variation as the measure of dispersion.
The record also lists pharmacokinetic outcomes concerning the timing of peak concentration, exposure over specified intervals, half-life, apparent clearance, and apparent volume of distribution. It includes measures for itraconazole and hydroxy-itraconazole as well. These outcomes provide a broader description of drug exposure and disposition, but their numerical findings are not reported in the registry record. Consequently, the central question can be identified from the study design, but the magnitude and precision of any difference cannot be determined from the posted results.
3. Trial Design
This completed phase 1 study enrolled 16 healthy participants. The registry record describes it as open-label, with a single-group model, no masking, and a fixed sequence across 2 periods. Participants received cobimetinib and itraconazole as part of a drug-interaction study involving multiple repeating doses. The stated purpose was to investigate the effect of co-administration of itraconazole on cobimetinib pharmacokinetics.
The study is not described as a randomized, parallel-group comparison. Instead, the primary outcome is framed as cobimetinib Cmax with and without itraconazole in the study’s fixed sequence. A fixed sequence means the conditions are encountered in a specified order rather than assigned randomly; the order itself is not reported in the registry record. Because the sequence is not randomized, changes between periods may be intertwined with changes in treatment condition. The registry record does not describe procedures for addressing period or sequence effects.
The study began in 2013-07, reached primary completion in 2013-10, and is listed as completed. The primary endpoint timeframe specifies measurements on Day 1 in Period 1 and on Day 4 in Period 2, with blood-sampling times extending from predose through 192 hours in Period 1 and through 240 hours in Period 2. These are the recorded sampling schedules, not evidence that every participant contributed a measurement at every time point.
The primary pharmacokinetic population was defined as participants who received at least 1 dose of cobimetinib and had evaluable pharmacokinetic data. The number meeting that definition is not reported in the registry record. The record lists one combined intervention arm, Cobimetinib + Itraconazole, and does not provide separate parallel-group arm descriptions. It reports 10 outcome measures and 3 analyses, but numerical pharmacokinetic results 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.
Period 1
| Stage | Cobimetinib + Itraconazole |
|---|---|
| STARTED | 16 |
| COMPLETED | 16 |
| NOT COMPLETED | 0 |
Period 2
| Stage | Cobimetinib + Itraconazole |
|---|---|
| STARTED | 16 |
| COMPLETED | 15 |
| NOT COMPLETED | 1 |
Reasons for not completing this period:
| Reason | Cobimetinib + Itraconazole |
|---|---|
| Non-Compliance | 1 |
Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population consisted of all participants who received at least 1 dose of cobimetinib and had evaluable PK data.
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: Safety population consisted of all participants who received at least 1 dose of cobimetinib and had at least 1 postdose safety assessment.
| Characteristic | Unit | Cobimetinib + Itraconazole |
|---|---|---|
| Participants analysed | 16 | |
| Age, Continuous | years | 38 (SD 9.9) |
| Sex: Female, Male: Female | Participants | 5 |
| Sex: Female, Male: Male | Participants | 11 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole, measured over Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | nanogram per milliliter (ng/mL) |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is maximum observed plasma concentration, or Cmax, of cobimetinib with and without itraconazole. It measures the highest concentration observed in the scheduled plasma samples during the assessment period. The registry record specifies nanograms per milliliter (ng/mL) as the unit and describes the summary as a geometric mean with geometric coefficient of variation.
Cmax is used in pharmacokinetic studies to describe peak observed exposure. Comparing this measure under conditions with and without a co-administered drug can help characterize whether the observed peak concentration differs between those conditions. This is a general explanation of the endpoint; a difference in Cmax alone does not establish the clinical importance of a drug interaction.
The recorded primary outcome description says Cmax was assessed using a model-independent approach. The sampling schedule spans predose and multiple postdose times in each period, allowing the observed maximum to be identified from concentration measurements. The record does not report the numerical geometric means, geometric coefficients of variation, treatment contrast, confidence interval, or test result. It therefore does not establish the size or precision of the observed contrast.
The endpoint is specific to cobimetinib concentration in plasma among participants in the defined pharmacokinetic population. It is not a measure of a clinical outcome, and the registry record does not describe a threshold for interpreting a particular Cmax value.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record establishes the question, population, endpoint, and general design: a completed open-label phase 1 study in 16 healthy participants, intended to evaluate cobimetinib pharmacokinetics with and without itraconazole. It identifies Cmax as the primary outcome and describes its summary as a geometric mean with geometric coefficient of variation. However, the numerical primary results are not reported in the registry record. There is no posted Cmax estimate for either condition and no reported treatment contrast, confidence interval, or p-value.
That absence limits interpretation. Without the estimates for the two conditions or a contrast between them, the direction and magnitude of any observed difference cannot be described. Without an uncertainty interval, the precision of an estimate cannot be assessed. No conclusion about the strength of evidence for a difference can be drawn from a primary endpoint result that is not reported. This is not evidence that the conditions were equivalent; the registry record simply does not report the information needed to assess the comparison.
The record lists secondary pharmacokinetic outcomes, including Tmax, AUC (0-t), half-life, apparent clearance, and apparent volume of distribution for cobimetinib, as well as concentration and exposure measures for itraconazole and hydroxy-itraconazole. Their numerical results are also not reported in the registry record. The presence of an outcome in the registry describes what was assessed, not what value was observed or whether a comparison was statistically persuasive.
Several features of the design matter when considering what a reported contrast might mean. The comparison is within a fixed sequence rather than a randomized parallel-group comparison. This can support measurement of each participant under different conditions, but fixed order means treatment condition and period may be linked. The registry record does not report analyses of period effects, carryover, or other sequence-related considerations. It also does not report the number of participants with evaluable pharmacokinetic data, so the analyzed population cannot be confirmed from the enrollment count alone.
General statistical interpretation: an estimate describes the observed contrast, while a confidence interval describes the range of values compatible with the data under the model and assumptions used. Neither is reported for the primary endpoint in the registry record. A p-value, if reported, would address compatibility with a specified null hypothesis under an analysis framework; it would not by itself describe the size or practical importance of an effect. No p-value for the primary comparison is reported.
The study is in healthy participants and is described as a pharmacokinetic interaction study. Its registry record does not report clinical efficacy outcomes or establish how any concentration difference relates to clinical outcomes. As a result, the posted record supports a description of the research question and design, but not a quantitative account of the observed pharmacokinetic effect or its clinical implications.
9. Statistical Methods Explained
The registry record characterizes the primary outcome as a model-independent assessment of cobimetinib Cmax. It reports a geometric mean as the summary measure and geometric coefficient of variation as the dispersion measure. It does not describe a model-based treatment comparison, a confidence-interval method, or a hypothesis test for the primary endpoint. The numerical primary results are not reported in the registry record.
What does Cmax represent?
Cmax is the largest observed plasma concentration within the sampling schedule. It is a measure of peak observed concentration rather than total exposure over time. The scheduled measurements included predose and postdose sampling in both periods. General explanation: a denser or differently timed sampling schedule can affect how well a measured maximum captures the true peak, because the maximum in a set of samples is not necessarily the exact peak between sampling times. The registry record gives the sampling times but does not report whether every planned sample was collected or how missing samples were handled.
Why use a geometric mean?
A geometric mean summarizes positive measurements on a multiplicative scale. General explanation: pharmacokinetic measurements may be summarized this way when proportional differences are more meaningful than absolute differences, and when values are better represented after logarithmic transformation. The record names a geometric mean but does not state the precise calculation procedure or report the resulting values. It also does not specify whether a treatment contrast was calculated on the original or transformed scale.
The geometric coefficient of variation describes dispersion relative to the geometric mean. General explanation: dispersion is important because an average alone does not show how variable participant measurements are. The record identifies this measure for the primary endpoint but does not report its numerical value.
What does model-independent assessment mean?
General explanation: a model-independent pharmacokinetic approach derives measures from observed concentration-time data without requiring a particular compartment model to describe the concentration curve. A directly observed maximum such as Cmax can be identified from measured concentrations. Other listed outcomes, such as area under the curve, half-life, clearance, and volume of distribution, involve their own definitions and estimation procedures. The registry record names these outcomes but does not provide detailed calculation algorithms, assumptions, or numerical results. It would therefore be inappropriate to infer the exact analysis steps from the outcome names alone.
How should the comparison design be understood?
The record describes a single-group, open-label, fixed-sequence study with 2 periods. The primary question compares cobimetinib with and without itraconazole. This is not a randomized parallel-arm comparison. General explanation: in a within-participant comparison, measurements under different conditions can be related to the same participant, which may reduce the influence of stable differences between participants. A fixed sequence, however, makes treatment condition occur alongside period, so time or order-related changes may complicate interpretation. The registry record does not report a method for separating these effects, and the treatment order is not reported.
The endpoint description names a pharmacokinetic population consisting of participants who received at least 1 dose of cobimetinib and had evaluable pharmacokinetic data. This defines who could contribute to the primary analysis, but the number meeting the definition and the handling of participants without evaluable data are not reported in the registry record.
What can planning illustrations show?
General explanation: sample-size calculations can illustrate how many participants per arm might be needed under specified assumptions to detect an effect at a chosen power and significance level. The planning illustration associated with this study is described as using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such an illustration is not the trial’s original design justification, and it is not observed power. The registry record does not report a sample-size justification for the study, and the numerical effect estimate and planning results are not reported in the registry record.
For an actual comparison, interpretation would ordinarily consider the estimate, its uncertainty, and the analysis population, alongside the design and assumptions. Those numerical details are unavailable in the registry record. The described statistical summaries therefore identify how the endpoint was framed, but they do not allow reconstruction of a quantitative result.
10. Multiplicity, Missing Data and Analysis Populations
The registry record names a primary endpoint, cobimetinib Cmax with and without itraconazole, and lists secondary pharmacokinetic outcomes. These include cobimetinib Tmax, AUC (0-t), half-life, apparent clearance, and apparent volume of distribution, along with Cmax, Tmax, and AUC (0-24) for itraconazole and hydroxy-itraconazole. It does not report a multiplicity adjustment, a hierarchy of secondary tests, or a strategy for controlling the chance of false-positive findings across multiple outcomes. These procedures are not reported in the registry record.
General explanation: when several outcomes or comparisons are tested, the chance of at least one apparently unusual result can increase if each is assessed independently. Prespecified testing order or multiplicity adjustment can address this issue, but the registry record does not say whether such procedures were used. The existence of multiple listed outcomes alone does not establish that each was tested inferentially or that a particular correction was required.
The primary endpoint population is described as participants who received at least 1 dose of cobimetinib and had evaluable pharmacokinetic data. The number in that population is not reported in the registry record. The record does not describe missing-data rules, exclusions from the pharmacokinetic analyses, treatment of measurements below quantification limits, or whether any participants discontinued or lacked samples. Those details are not reported in the registry record.
The overall enrollment count is 16, but enrollment should not be treated as the number analyzed for every outcome. The analysis population depends on the stated evaluability criterion, and outcome-specific analysis counts are not reported. Without those counts and missing-data procedures, the amount of information contributing to each pharmacokinetic summary cannot be assessed.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Cobimetinib + Itraconazole | 0 | 16 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cobimetinib + Itraconazole | 6 of 16 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cobimetinib + Itraconazole |
|---|---|---|
| Abdominal pain | Gastrointestinal disorders | 1 of 16 |
| Diarrhoea | Gastrointestinal disorders | 1 of 16 |
| Dyspepsia | Gastrointestinal disorders | 1 of 16 |
| Erythema | Skin and subcutaneous tissue disorders | 1 of 16 |
| Rash macular | Skin and subcutaneous tissue disorders | 1 of 16 |
| Alanine aminotransferase increased | Investigations | 1 of 16 |
| Aspartate aminotransferase increased | Investigations | 1 of 16 |
| Dizziness | Nervous system disorders | 1 of 16 |
| Headache | Nervous system disorders | 1 of 16 |
| Rhinitis | Infections and infestations | 1 of 16 |
The registry record reports 16 participants at risk for serious adverse events in the combined Cobimetinib + Itraconazole group and 0 participants affected by a serious adverse event. It reports 16 participants at risk for other adverse events and 6 participants affected. The record does not provide serious adverse event terms; those terms are not reported in the registry record. The death count is not reported in the registry record.
These are participant counts, not measures of event severity beyond the serious-versus-other classification. The record does not state how many total events occurred, whether an individual could have had more than one event, when events arose, or whether investigators considered events related to either drug. It also does not describe the criteria used to classify seriousness in the displayed safety record.
General explanation: a count of participants affected indicates how many people had at least one event in the recorded category, while an event count may include repeated events in the same person. Those quantities are not interchangeable. The reported 0 serious adverse event participants should be read as the registry’s recorded count for this study group, not as proof that serious events are impossible or that the treatment conditions have no risk. Safety findings from this small healthy-participant study also do not establish safety in other populations.
12. What the Result Does, and Does Not, Mean
This trial is relevant because it was designed to examine a specific pharmacokinetic question: whether cobimetinib exposure, assessed primarily through maximum observed plasma concentration, differed with versus without itraconazole in healthy participants. The record identifies a phase 1, open-label, fixed-sequence design and reports enrollment of 16 participants. It also specifies a pharmacokinetic population based on receiving at least 1 dose of cobimetinib and having evaluable data.
What the registry record does not establish is the observed size, direction, or precision of the primary comparison. Numerical Cmax values, a treatment contrast, uncertainty intervals, and test results are not reported in the registry record. Accordingly, the record cannot support a quantitative conclusion about how much the measured peak concentration changed or how certain an estimate would be. The absence of those results should not be interpreted as a finding of no difference.
The endpoint measures plasma concentration, not clinical benefit or harm. General explanation: pharmacokinetic measures help describe drug exposure, but their clinical interpretation depends on additional information, such as the relationship between exposure and outcomes. That relationship is not reported in the registry record. The study’s healthy-participant population also differs from a population receiving treatment for a disease, and the record does not establish that its findings apply beyond the participants studied.
The record lists additional pharmacokinetic outcomes for cobimetinib, itraconazole, and hydroxy-itraconazole, but it does not provide their numerical findings. It also does not report the analyzed population size, missing-data procedures, or multiplicity strategy. These gaps limit assessment of the completeness and uncertainty of the posted analyses.
The safety record reports no participants affected by a serious adverse event and reports 6 participants affected by other adverse events among 16 at risk in the combined group. These figures describe the recorded counts; they do not establish causation or characterize event details that are not reported. Overall, the record documents the study question and selected design and safety information, but it does not provide the numerical pharmacokinetic results needed to answer the primary question quantitatively.
13. Why This Trial Matters Statistically
Drug-interaction studies pose a focused statistical question: how does a pharmacokinetic measure under one exposure condition compare with the measure under another? This study’s primary outcome, cobimetinib Cmax with and without itraconazole, makes that contrast explicit. Its fixed-sequence, 2-period structure also illustrates why design details matter when interpreting a within-participant comparison.
General explanation: a within-participant design can account for stable differences between people because each participant contributes measurements under more than one condition. But fixed treatment order can link the exposure condition with period, so time-related changes and treatment condition may be difficult to distinguish. The registry record does not report the treatment order or methods addressing period effects. Recognizing this design feature is important before interpreting a numerical comparison, if one is available.
The study also illustrates the distinction between naming an endpoint and reporting its evidence. The record specifies a geometric mean, geometric coefficient of variation, and model-independent approach for Cmax. Those details clarify the type of summary planned, but they do not substitute for the actual estimates, uncertainty intervals, or analysis population counts. Since the numerical pharmacokinetic results are not reported in the registry record, the size and precision of the primary comparison remain unknown.
Finally, the record lists several secondary pharmacokinetic outcomes and a safety summary. Multiple outcomes can broaden the description of exposure, but they raise questions about analysis plans, missingness, and multiplicity that the record does not resolve. This study is therefore a useful example of reading a registry as a description of design and registered outcomes while distinguishing that information from the quantitative evidence needed to interpret a drug-interaction estimate.
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 central limitation for interpreting this study from its registry record is that numerical pharmacokinetic results are not reported. The record names Cmax as the primary endpoint and describes its summary method, but it does not give condition-specific estimates, a contrast, uncertainty intervals, or a test result. The listed secondary pharmacokinetic measures also lack numerical results. Thus, neither the magnitude nor precision of the intended comparisons can be assessed.
The study enrolled 16 participants, but the number in the defined pharmacokinetic population is not reported in the registry record. The record does not explain missing samples, exclusions, outcome-specific analysis counts, or handling of measurements outside quantification limits. The degree to which available data may have differed from planned data therefore cannot be evaluated.
The design was open-label and fixed sequence, not randomized. The registry record does not report the order of conditions or analysis procedures for period, sequence, or carryover effects. These omissions prevent a detailed assessment of how the design’s timing features were handled.
The record does not report a sample-size justification, a statistical testing plan, or a multiplicity strategy. It also does not describe confidence-interval procedures or provide details sufficient to reproduce the pharmacokinetic calculations. The planning illustration is not the study’s design justification and is not observed power.
Finally, the participants were healthy, and the listed primary outcome is a plasma concentration measure. The record does not report clinical outcomes or explain how pharmacokinetic differences relate to clinical consequences. The safety summary gives counts but not event terms or attribution. These are limitations of what can be concluded from the registry record, not evidence that unreported methods or results did not exist.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study to Evaluate Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Participants — NCT01929876.
- Registry record last updated 2016-08-04; status last verified 2016-06.
- Results first posted 2016-08-04.
- 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.
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18. Record Summary
NCT01929876 is a completed phase 1, open-label study sponsored by Genentech, Inc. It enrolled 16 healthy participants and examined the effect of itraconazole co-administration on cobimetinib pharmacokinetics. The record describes a single-group, fixed-sequence study with 2 periods and multiple repeating doses.
The primary outcome was cobimetinib Cmax with and without itraconazole, summarized as a geometric mean with geometric coefficient of variation using a model-independent approach. The pharmacokinetic population was defined by receipt of at least 1 dose of cobimetinib and evaluable pharmacokinetic data. Its size and the numerical primary and secondary results are not reported in the registry record.
The safety record lists 0 participants with serious adverse events and 6 with other adverse events among 16 at risk in the combined group. Serious event terms and the death count are not reported in the registry record. The record does not report multiplicity procedures, missing-data methods, or a sample-size justification.