Dose Ranging Pharmacokinetics and Pharmacodynamics Study With Mepolizumab in Asthma Patients With Elevated Eosinophils: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Ranging Pharmacokinetics and Pharmacodynamics Study With Mepolizumab in Asthma Patients With Elevated Eosinophils (NCT01366521), a randomized phase 2 study. The primary outcome is Change From Baseline in Blood Eosinophil Levels at Week 12 (Day 84).

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, open-label, parallel-group study of mepolizumab in adults with asthma and elevated blood eosinophil levels. The registry lists planned enrollment of 70 and records the study as completed. The study began in 2011-02, with primary completion in 2012-03.

The four listed groups received 12.5 mg subcutaneously, 125 mg subcutaneously, 250 mg subcutaneously, or 75 mg intravenously. The study description says participants were to receive 3 doses 28 days apart. Masking was none, so the study was open-label. Allocation was randomized, and the record identifies a parallel-group model.

The primary outcome was change from baseline in blood eosinophil levels at Week 12, also identified as Day 84. The reported primary estimates are based on a nonlinear dose-response model. The listed analysis counts are 20.0 for 12.5 mg subcutaneous, 14.0 for 125 mg subcutaneous, 21.0 for 250 mg subcutaneous, and 11.0 for 75 mg intravenous. These are the group counts associated with the posted primary outcome; they should not be treated as a substitute for the record’s planned enrollment.

The study also included pharmacokinetic, pharmacodynamic, immunogenicity, safety, and tolerability assessments. Secondary outcomes include laboratory findings outside the normal range, blood pressure, heart rate, anti-mepolizumab antibodies, electrocardiogram findings, and measures of subcutaneous bioavailability compared with intravenous dosing. The registry record does not report a placebo 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: A total of 70 participants were enrolled into the study and 66 participants completed the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacodynamic (PD) Population: all participants randomized to treatment and who received at least one dose of study medication and who also had a Baseline PD or biomarker measurement and at least one post-treatment PD or biomarker measurement. Only participants who were available at the specified time point were analyzed.

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 Change From Baseline in Blood Eosinophil Levels at Week 12 (Day 84), measured over Baseline (Day 1 pre-dose) and Week 12.

The primary endpoint was change from baseline in blood eosinophil levels at Week 12, or Day 84. The registry describes the outcome as the proportion of baseline blood eosinophil and defines change as the post-baseline value minus the baseline value. This endpoint is a pharmacodynamic measure: it tracks a biological measurement over the treatment period rather than a clinical event or symptom outcome.

Blood eosinophil levels were selected to assess the pharmacodynamic response across the dose groups. The registry says the change from baseline in log-transformed levels was analyzed with linear and nonlinear dose-response models. The dose response was found to be nonlinear, so only the nonlinear model results are reported. The model also included an adjustment for baseline eosinophil count.

The posted estimates are 0.43 for 12.5 mg subcutaneous, 0.14 for 125 mg subcutaneous, 0.12 for 250 mg subcutaneous, and 0.14 for 75 mg intravenous. Their unit is a proportion of baseline, and each is accompanied by a 95% confidence interval. These estimates describe the modeled endpoint on the registry’s stated scale; they are not absolute eosinophil counts. The endpoint does not by itself establish how participants felt or whether clinical outcomes changed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a dose-response model do?

The registry reports that the change from baseline in log-transformed blood eosinophil levels at Week 12 was analyzed using a linear model and a nonlinear Imax dose-response model. The dose response was found to be nonlinear, and only results from the nonlinear model are presented. General statistical explanation: a dose-response model describes how an outcome is related to dose. A linear form assumes a constant change in outcome for a given change in dose; a nonlinear form allows the relationship to bend or level off. The Imax model is one way to represent a nonlinear dose response.

The posted group values are model-based estimates, rather than raw arithmetic averages of the observed blood eosinophil measurements. The registry does not report the model parameter estimates, the full equation, or a detailed account of model fitting. It also does not report a direct statistical test comparing the groups. The plotted or tabulated estimates should therefore be interpreted as the model’s summary of the dose-response pattern, with the stated confidence intervals.

Why transform the outcome?

The registry states that blood eosinophil levels were log-transformed before analysis. General statistical explanation: a logarithmic transformation changes the scale on which the model works. It can be useful when measurements are skewed or when differences in the original scale are not well represented by a linear model. The transformation also affects how estimates should be interpreted: a modeled result on a transformed scale is not automatically an absolute difference in the original measurement units.

Zero values were imputed with half the minimum value across all dose groups and time points before the log10 transformation. This is a stated data-processing step for handling zeros, since the logarithm of zero is not defined. The registry record does not give the minimum value used, the number of zero measurements, or additional detail about how this imputation affected the model estimates.

How should the confidence intervals be read?

Each primary endpoint estimate is reported with a 95% confidence interval. General statistical explanation: a confidence interval gives a range of values compatible with the estimate under the statistical model and its assumptions. A narrower interval indicates greater precision around that estimate than a wider interval, though it does not eliminate uncertainty. The interval is not a guarantee that the true value lies within its endpoints, and it does not by itself answer whether two treatment groups differ.

The reported intervals are 0.31 to 0.58 for 12.5 mg subcutaneous, 0.11 to 0.17 for 125 mg subcutaneous, 0.1 to 0.15 for 250 mg subcutaneous, and 0.12 to 0.17 for 75 mg intravenous. The record does not state the method used to calculate these intervals. It also does not provide p-values or a reported hypothesis test for differences between these estimates.

Why adjust for baseline?

The primary model incorporated an adjustment for baseline eosinophil count. General statistical explanation: baseline adjustment can account for differences in starting measurements when estimating an outcome after treatment. It can improve precision when baseline values are related to follow-up values. The registry does not report the adjustment’s coefficient or describe further model covariates, so the specific contribution of the adjustment cannot be assessed from the record.

The study also assumed that 75 mg intravenously equated to 100 mg subcutaneously within the model. This places the intravenous group on the model’s dose scale alongside the subcutaneous groups. It is an explicit modeling assumption. The record does not report a sensitivity analysis examining other ways of relating the routes or doses.

What does over-dispersion mean in general?

General statistical explanation: over-dispersion occurs when observed variability is greater than a statistical model expects. It is relevant to some types of count or binary outcomes, where an overly restrictive model can make uncertainty appear smaller than it is. The primary endpoint is a modeled blood eosinophil measure, and the registry does not report an over-dispersion assessment or a count-model method. It would not be appropriate to infer that over-dispersion was tested or present.

The posted primary outcome has no single two-arm comparison, and the registry lists no separate analysis records. The record also does not report a statistical analysis plan, a sample-size justification, interim analyses, or a prespecified method for handling multiple outcomes. Those omissions limit what can be said about the intended inferential framework beyond the model description and confidence intervals that are recorded.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures and 8 posted secondary outcomes. These include laboratory safety measures, blood pressure and heart rate, antibodies, electrocardiogram findings, and pharmacokinetic measures of subcutaneous bioavailability. The record does not report how multiplicity across these outcomes was addressed. It is therefore not possible to determine whether any adjustment was planned or whether the outcomes were treated as exploratory.

No separate analysis records are listed. The primary outcome description does not provide p-values or a reported test comparing the dose groups. The registry record does not report an interim-analysis plan or a complete statistical analysis plan. It also does not report a sample-size justification for the primary endpoint, so the enrollment figure cannot be taken as evidence of a particular power calculation.

The primary analysis population is described as participants randomized to treatment who received at least one dose and had a baseline pharmacodynamic or biomarker measurement and at least one post-treatment measurement. The population description is incomplete after stating that only participants available at the specified time points were included. Further details about missing observations, withdrawals, or the handling of participants without a Week 12 measurement are not reported in the registry record.

The model’s zero-value handling is described: zeros were imputed with half the minimum value across dose groups and time points before log10 transformation. That step is distinct from handling missing values. The registry does not report how missing endpoint data were imputed, whether a sensitivity analysis was conducted, or how departures from the stated analysis population affected the results.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bladder papilloma (4.8%).

The registry reports serious adverse event counts by group, alongside the number at risk. For 12.5 mg subcutaneous, 1 participant was reported with a serious adverse event among 21 at risk. For 125 mg subcutaneous, the count was 0 among 15 at risk; for 250 mg subcutaneous, it was 0 among 23 at risk; and for 75 mg intravenous, it was 0 among 11 at risk. The record also gives an overall subcutaneous group count of 1 among 59 at risk. That overall entry includes the subcutaneous groups and should not be added to the group entries.

The registry lists Bladder papilloma as a top serious adverse event term, with 4.8%. It does not identify a group for that term in the registry record. The definitions and collection rules used for serious adverse events are not reported in the registry record. Death counts are also not reported in the posted safety results.

These are descriptive counts from a study with the listed group sizes, not a definitive comparison of safety between regimens. The counts do not establish whether an event was caused by treatment. Other adverse events are also reported: the number affected is 14 among 21 at risk in the 12.5 mg subcutaneous group, 7 among 15 in the 125 mg subcutaneous group, 12 among 23 in the 250 mg subcutaneous group, and 6 among 11 in the intravenous group.

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

The primary results describe modeled blood eosinophil values at Week 12 relative to baseline across four mepolizumab dose-and-route groups. The estimate for 12.5 mg subcutaneous is 0.43, while the estimates for 125 mg subcutaneous, 250 mg subcutaneous, and 75 mg intravenous are 0.14, 0.12, and 0.14, respectively. Each has a reported 95% confidence interval. This pattern is the statistical result recorded for the biomarker endpoint.

The results do not establish a statistically significant difference between any pair of groups. No pairwise test or p-value is reported. They also do not show how any regimen compares with placebo or no treatment, because no such group is listed. The intravenous estimate is part of a dose-response model that assumes 75 mg intravenously corresponds to 100 mg subcutaneously; it is not a direct comparison at equal nominal doses.

The endpoint is a pharmacodynamic biomarker, not a measure of asthma symptoms, exacerbations, quality of life, or another clinical outcome. The registry record does not provide results for those outcomes in the primary endpoint data. A change in a biomarker cannot by itself establish a change in how participants feel or function.

The confidence intervals describe precision under the fitted model, but do not resolve uncertainty about model assumptions, missing measurements, or the broader set of outcomes. The record does not report multiplicity handling, a detailed missing-data method, or a complete statistical analysis plan. The findings should therefore be read as a dose-ranging pharmacodynamic description from this study, not as a comprehensive estimate of clinical benefit or harm.

13. Why This Trial Matters Statistically

This study is statistically notable for presenting a dose-response analysis rather than reducing the primary result to a single two-group comparison. The registry reports that both linear and nonlinear models were considered, that the response was judged nonlinear, and that only the nonlinear model results were presented. This makes the model choice central to how the primary estimates should be understood.

The results also illustrate how a model can place different administration routes on a shared dose scale through an assumption. The analysis treated 75 mg intravenously as corresponding to 100 mg subcutaneously. That choice allows the intravenous group to be represented within the dose-response model, but it should remain visible when interpreting the estimate rather than being mistaken for a direct equal-dose comparison.

Log transformation and zero imputation are further important features of the analysis. The registry specifies that zeros were replaced with half the minimum value across groups and time points before transformation. This explains part of the data-processing approach, while leaving the number of zero values and the influence of that step unreported.

Finally, the record gives group estimates and confidence intervals without a reported pairwise test, p-value, or multiplicity approach. This distinction matters: a pattern across modeled estimates can be described, but inferential claims about differences require an analysis that the registry does not report. The trial is therefore informative as a pharmacodynamic dose-ranging record, while its posted statistical detail limits conclusions about comparative uncertainty.

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 a complete statistical analysis plan, sample-size justification, interim analyses, or a formal hypothesis test for the primary outcome. It provides modeled estimates and confidence intervals but no p-values or reported comparisons between dose groups. Multiplicity handling across the listed outcomes is not reported.

The primary population description ends with an incomplete statement about participants available at specified time points. The record does not explain how missing Week 12 measurements, withdrawals, or other incomplete follow-up were handled. Although the primary outcome description specifies an imputation for zero values before log transformation, it does not report the number of zero values or a sensitivity analysis for that choice.

The model’s nonlinear form was selected after the dose response was found to be nonlinear, but the record does not provide the model equation, parameter estimates, or a model-fit assessment. It also does not report sensitivity analyses for the assumption that 75 mg intravenously equates to 100 mg subcutaneously. The posted estimates consequently depend on modeling decisions that cannot be fully evaluated from the registry record.

The study was open-label and the record lists active mepolizumab groups without a placebo group. The primary endpoint is a pharmacodynamic blood measure, and the posted primary results do not provide a clinical outcome comparison. The safety entries are descriptive counts, with no reported causal attribution or detailed event definitions. These limitations constrain interpretation of both comparative effects and the broader clinical meaning of the results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dose Ranging Pharmacokinetics and Pharmacodynamics Study With Mepolizumab in Asthma Patients With Elevated Eosinophils — NCT01366521.
• Registry record last updated 2017-01-11; status last verified 2016-11.
• Results first posted 2015-12-10.
• 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

NCT01366521 is a completed, randomized, open-label, parallel-group phase 2 study of mepolizumab in adults with asthma and elevated blood eosinophil levels. Planned enrollment was 70. The study began in 2011-02 and reached primary completion in 2012-03.

The four listed regimens were 12.5 mg, 125 mg, or 250 mg subcutaneously, and 75 mg intravenously. The study description specifies 3 doses 28 days apart. The primary endpoint was change from baseline in blood eosinophil levels at Week 12, analyzed with a nonlinear dose-response model and reported with 95% confidence intervals.

The registry also lists safety, laboratory, cardiovascular, immunogenicity, electrocardiogram, and pharmacokinetic outcomes. It does not report a placebo group, a formal primary between-group test, multiplicity handling, or a complete missing-data method.