Pharmacokinetic Study Comparing MB02 And US And EU Avastin® In Healthy Male Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetic Study Comparing MB02 And US And EU Avastin® In Healthy Male Volunteers (NCT04238663), a randomized phase 1 study. The primary outcome is Cmax: Maximum Observed Serum Concentration.

2. Clinical Question

This is a pharmacokinetic comparison, not a trial of clinical benefit in people with a disease. The central question concerns measured drug concentration in blood after administration. The endpoint is Cmax, the maximum observed serum concentration, and the registry describes the bioequivalence assessment as based on 90% confidence intervals for ratios of geometric least-squares means. The stated limits are 0.80 to 1.25.

Safety and immunogenicity were also evaluated. The listed secondary outcomes include other pharmacokinetic measures, anti-bevacizumab antibodies, and treatment-emergent adverse events. Those outcomes provide additional descriptions of the study groups, but they are distinct from the primary Cmax comparison. The registry record does not report a clinical efficacy question or a patient health outcome as the primary endpoint.

3. Trial Design

The registry describes a randomized, double-blind, parallel-group, single-dose, three-arm Phase 1 study. It enrolled 115 healthy male volunteers. The listed study status is completed; the recorded start date is 2019-09-24 and the primary completion date is 2020-03-17. The sponsor is mAbxience Research S.L.

Participants were allocated to MB02, EU-approved Avastin®, or US-licensed Avastin®. Each arm description specifies a single 3mg/kg dose, delivered as a 90-minute infusion on day 1. The products were described as posted in sterile vials of 400mg/16ml. Randomization is recorded as the allocation method, masking as triple, and the model as parallel. The registry does not define which roles were masked, so the meaning of triple masking beyond the recorded label is not reported in the registry record.

The primary endpoint was Cmax, or maximum observed serum concentration. Blood sampling was planned predose, at 1.5 hours at the end of infusion, and at 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose, with further sampling on Day 3-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100. The registry lists additional pharmacokinetic, immunogenicity, and safety outcomes.

The posted Cmax arm summaries each report n=38. The registry gives an overall enrollment of 115, but the reason for the difference between overall enrollment and the arm-level endpoint counts is not reported in the registry record. Details of the randomization sequence, allocation concealment, and the analysis populations are also 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: One subject in the US Avastin arm withdrew before receiving any study treatment.

Overall Study

Reasons for not completing this period:

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: Maximum Observed Serum Concentration, measured over Predose, 1.5 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100..

Cmax is the maximum observed serum concentration of the study drug after dosing. It summarizes the highest measured concentration reached during the sampling period. In this trial, blood was sampled at multiple time points after infusion, so Cmax depends on observed concentration measurements rather than on a single scheduled collection. The registry records its unit as (ng/mL)/(mg/mL) and describes the reported arm statistic as a geometric least-squares mean with geometric coefficient of variation as the dispersion measure.

Cmax is used in pharmacokinetic comparisons because it describes peak exposure. The registry's stated purpose was to compare the pharmacokinetic profiles of MB02, US Avastin®, and EU Avastin® and assess bioequivalence between the arms. For that assessment, the record describes comparing ratios of geometric least-squares means and judging similarity against predefined limits of 0.80 to 1.25, using 90% confidence intervals.

In general, a confidence interval expresses the range of values compatible with the analysis and its assumptions at the stated confidence level. For this endpoint, the relevant question is whether the entire interval for a ratio lies within both bioequivalence limits. The endpoint does not, on its own, describe every aspect of drug exposure, safety, immunogenicity, or clinical outcomes. The registry lists additional measures, including AUC(0 t), clearance, half-life, time to maximum concentration, antibodies, and adverse events.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The central statistical feature is a comparison of geometric least-squares means through ratios and confidence intervals. The registry says that the primary Cmax comparison followed regulatory bioequivalence guidelines: two treatments are judged not to be different for this purpose when the 90% confidence interval for the geometric least-squares mean ratio is fully contained within the limits of 0.80 to 1.25. This is an interval-based decision rule, not simply a test of whether a conventional difference is statistically distinguishable from zero.

Why use a ratio?

Concentration measures are often analyzed on a scale where relative differences are meaningful. A ratio compares the estimated geometric mean in one group with that in another. A ratio of 1 represents equal estimates on that scale; values on either side indicate the direction and relative size of the contrast. The reported comparisons are MB02 versus EU-approved Avastin®, MB02 versus US-licensed Avastin®, and EU-approved versus US-licensed Avastin®. The registry reports ratios of 1.06, 0.983, and 0.926, respectively.

For bioequivalence, similarity is not inferred merely because an analysis fails to identify a difference. Instead, the confidence interval must be sufficiently narrow and positioned so that its entire range is inside the acceptable limits. An interval can include 1 and still fail that criterion if it extends beyond a limit. In this study, all three reported intervals are entirely within 0.80 to 1.25: 0.976 to 1.16, 0.897 to 1.08, and 0.851 to 1.01. This supports the interval-based conclusion for the reported Cmax comparisons, under the stated rule and analysis.

What does a confidence interval convey?

In general, a confidence interval communicates uncertainty around an estimate. Its width reflects the precision of the estimate under the analysis and its assumptions. A narrower interval indicates greater precision than a wider interval, while an interval that crosses a decision boundary may leave the criterion unresolved. A 90% confidence interval does not mean there is a 90% probability that the fixed true ratio lies inside this particular calculated interval. It is a procedure-based coverage statement when the method's assumptions hold.

The posted arm-level values are geometric least-squares means, and the dispersion measure is the geometric coefficient of variation. In general, geometric summaries are useful when measurements are positive and comparisons are naturally interpreted multiplicatively. A geometric coefficient of variation describes spread relative to a geometric scale; it is not the same quantity as the confidence interval around a ratio. The registry record does not explain the transformation, fitted model, covariates, or method used to calculate the least-squares means and intervals.

Why can variability matter?

General statistical principle: greater variability makes it harder to estimate a group contrast precisely, all else being equal. Pharmacokinetic measurements can vary between participants and across sampling times. The posted geometric coefficients of variation are 24.8 for MB02, 20.0 for EU-approved Avastin®, and 24.9 for US-licensed Avastin®. These figures describe variability as reported, but they do not disclose how variability was modeled or how missing measurements were handled. The width of each reported confidence interval gives a direct indication of the precision achieved for the corresponding ratio.

General statistical principle: over-dispersion arises when observed variability is greater than a model assumes. If present and not accommodated, standard errors may be too small and confidence intervals too narrow. The registry record does not report an over-dispersion assessment, so it is not possible to say whether it was evaluated or relevant to the analysis. The general concept should not be read as a finding about this trial.

What is not established by the interval criterion?

The interval-based result applies to the endpoint and comparisons reported. It does not establish equality of all participant-level concentration profiles, nor does it automatically extend to AUC, clearance, half-life, antibody outcomes, adverse events, or clinical outcomes. Each endpoint may have a different estimand, analysis population, and uncertainty. The registry record lists several secondary outcomes but does not report all their numerical results in the record summarized by these registry entries.

The record also does not state the statistical model, handling of below-quantification values, missing samples, exclusions, or multiplicity procedure. These details can affect how results are estimated and how broadly multiple comparisons should be interpreted. The posted intervals can be described accurately using the reported values and stated decision rule, but unreported analytic details should not be inferred.

10. Analyses Reported by the Sponsor

The registry reports the pairwise ratios and 90% confidence intervals as the study's Cmax comparison results. It does not identify a separate recalculated analysis in the registry record for this record, nor does it provide independently recalculated ratios or intervals. Accordingly, there is no recalculated numerical comparison to set alongside the reported analysis.

The listed arm-level geometric least-squares means and geometric coefficients of variation are not enough to reproduce the pairwise confidence intervals by themselves. Reproduction would require the analysis details and relevant data or model outputs, which are not reported in the registry record. The registry does not describe the estimation method for the pairwise analyses beyond naming the ratio of geometric least-squares means and the 90% confidence interval.

The reported intervals all fall within the registry's stated bioequivalence limits of 0.80 to 1.25. The discrepancy indicator is false, so the record does not flag a disagreement between a sponsor analysis and a recalculation. This interpretation therefore rests on the posted pairwise results, without claiming an independent recalculation or adding a separate estimate.

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint includes three pairwise comparisons among the three treatment groups. The registry reports a 90% confidence interval for each pair, and the stated bioequivalence criterion is applied to each interval. The record does not report whether the comparisons were designated in a hierarchy, whether multiplicity was addressed, or whether any adjustment to the interval procedure was made. Therefore, the three pairwise results should be read as the analyses recorded, without assuming an unreported family-wise error control strategy.

The registry lists eight outcome measures overall and six analyses. It also lists several secondary pharmacokinetic outcomes, immunogenicity, and treatment-emergent adverse events. The multiplicity approach for these outcomes is not reported in the registry record. When many endpoints or contrasts are considered, general statistical practice recognizes that the chance of at least one apparently notable result can increase unless the analysis plan accounts for the number and structure of comparisons. That general concern does not establish that any reported result is false; it is a reason to distinguish the primary question from exploratory or secondary findings.

Details about missing data are not reported in the registry record. The posted primary arm summaries report n=38 in each group, while overall enrollment is 115. The record does not explain which participants contributed to each endpoint, whether any concentration samples were missing, or how incomplete sampling was handled. It also does not identify whether analyses used an intention-to-treat, per-protocol, pharmacokinetic, or other population. These omissions limit assessment of how exclusions or incomplete data might affect the reported estimates.

General statistical principle: missing measurements can affect an estimate if their occurrence or values differ systematically from those observed. The degree of concern depends on the amount, reasons, timing, and analysis of missingness. Those details cannot be evaluated from the registry information; they are not reported in the registry record. No assumptions about the missing-data mechanism or analysis population should be substituted for that absent information.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The posted safety figures report zero serious adverse events among 38 participants in each group. They also report zero deaths in each group. These counts describe what was recorded for the study groups and do not establish that serious events are impossible or that the groups have identical safety profiles.

Other adverse events are reported for 30 participants in the MB02 group, 25 in the EU-approved Avastin® group, and 32 in the US-licensed Avastin® group, with 38 participants at risk in each group. The registry distinguishes these other events from serious adverse events. These counts should not be combined with the serious-event counts or interpreted as event rates without additional information about definitions, follow-up, event severity, and participant-level event totals.

With no serious events recorded in these groups, the study provides limited information about uncommon serious harms. In general, a zero count in a study of this size does not demonstrate zero underlying risk; the precision of safety estimates depends on the amount of exposure and the event frequency. The registry record does not provide serious-event terms because none are listed, and it does not provide further detail about the adverse-event collection or attribution process. These observations describe the posted safety counts and are not a clinical recommendation.

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

The primary Cmax results show that the three reported pairwise 90% confidence intervals lie within the registry's stated bioequivalence limits of 0.80 to 1.25. Under the criterion described in the record, the intervals support the stated bioequivalence assessment for Cmax among MB02, EU-approved Avastin®, and US-licensed Avastin®. This is a conclusion about the reported endpoint, comparisons, and analysis.

The confidence intervals also show that the ratios are estimated with uncertainty rather than known exactly. Their positions within the limits indicate that the uncertainty ranges reported for these comparisons satisfy the interval criterion. This does not prove that the true ratios equal 1, nor does it mean that every individual's concentrations were alike. Bioequivalence is evaluated against specified bounds, not by demanding exact numerical identity.

The result does not establish similarity for every pharmacokinetic measure. The registry lists time to maximum concentration, AUC(0 t), clearance, and terminal half-life as secondary outcomes, but their numerical results are not included in the registry record described for this analysis. It also lists immunogenicity and adverse events, which address distinct questions. Results for those outcomes cannot be inferred from the Cmax intervals.

The study involved healthy male volunteers and a single dose. The record does not report a clinical efficacy endpoint or results in patients being treated for a disease. Therefore, the pharmacokinetic comparison should not be interpreted as a statement about clinical benefit, treatment choice, or comparative effectiveness in a patient population. The safety counts are also limited by the study's size and duration as described in the record; uncommon events cannot be ruled out by the absence of recorded serious events.

Important design and analysis details are not reported in the registry record, including the full analysis population, handling of missing observations, model specification, and multiplicity approach. Those omissions do not change the values recorded for the Cmax comparisons, but they constrain independent assessment of how the estimates were produced and how broadly they should be generalized.

14. Why This Trial Matters Statistically

This study illustrates a distinction that is central to equivalence and similarity analyses: a lack of evidence for a difference is not the same as affirmative evidence that estimates are sufficiently similar. The registry uses a prespecified interval criterion. The relevant question is whether the whole confidence interval for each ratio is contained within defined limits, not merely whether the point estimate is near 1.

For Cmax, the reported intervals for MB02 versus EU-approved Avastin®, MB02 versus US-licensed Avastin®, and EU-approved versus US-licensed Avastin® are each fully within 0.80 to 1.25. Reading the point estimates together with their intervals makes the strength and precision of the reported evidence clearer than reading the arm means alone. The intervals support the criterion for the measured endpoint while still reflecting uncertainty.

The trial also offers a practical example of how a three-arm design yields multiple pairwise comparisons. Each contrast has its own estimate and uncertainty interval, and the comparisons should be identified explicitly rather than collapsed into one general claim. The record's lack of a reported multiplicity strategy and detailed analysis methods is a reminder that statistical interpretation depends not only on the numerical result but also on knowing how the analysis was planned and conducted.

Finally, pharmacokinetic similarity is a specific statistical and scientific question. Cmax describes peak measured concentration; it does not summarize all drug exposure, safety, immunogenicity, or clinical outcomes. Keeping the endpoint and population in view prevents a narrow pharmacokinetic result from being extended beyond what the registry reports.

15. 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 record reports the Cmax arm summaries and three pairwise confidence intervals, but it does not give the full statistical analysis plan or the method used to estimate the geometric least-squares means. Model specification, covariate adjustment, variance assumptions, and the precise calculation of standard errors are not reported in the registry record. These omissions limit independent reproduction and assessment of the reported intervals.

Overall enrollment is 115, whereas the posted Cmax arm summaries each report n=38. The record does not explain this difference or define the population used for the primary analysis. Reasons for exclusions, withdrawals, incomplete sampling, or endpoint-specific missingness are not reported in the registry record. The handling of concentrations below any quantification threshold is also not reported.

The registry gives a long sampling schedule, extending through Day 100, but does not provide sample completion information or details of how the observed maximum was determined when measurements were unavailable. It also does not report the multiplicity approach for the three pairwise primary comparisons or the several listed secondary outcomes.

The study was conducted in healthy male volunteers, and the intervention was a single dose. The record does not provide evidence from patients with a disease or from repeated dosing. Its primary endpoint is pharmacokinetic rather than clinical. The safety counts record no serious adverse events or deaths in the three groups, but the study cannot settle questions about rare events from these counts alone. These limitations define the scope of interpretation; they do not negate the posted Cmax results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pharmacokinetic Study Comparing MB02 And US And EU Avastin® In Healthy Male Volunteers — NCT04238663.
• Registry record last updated 2023-10-25; status last verified 2021-03.
• Results first posted 2021-02-24.
• 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.

19. Record Summary

NCT04238663 is a completed Phase 1 randomized, double-blind, parallel, three-arm, single-dose study sponsored by mAbxience Research S.L. It enrolled 115 healthy male volunteers and compared MB02 with EU-approved and US-licensed Avastin®. Each group received a single 3mg/kg infusion on day 1.

The primary endpoint was Cmax, maximum observed serum concentration. The registry reports geometric least-squares mean ratios and 90% confidence intervals for all three pairwise comparisons. Each interval is within the stated bioequivalence limits of 0.80 to 1.25. The record also lists other pharmacokinetic, immunogenicity, and safety outcomes.

No serious adverse events or deaths were recorded in the posted group counts. Further details of the analysis population, missing-data handling, statistical model, and multiplicity approach are not reported in the registry record.