Healthy
Conditions
Brief summary
This trial will investigate the pharmacokinetics and safety of BI 695502 and to establish pharmacokinetic biosimilarity of BI 695502 compared to bevacizumab.
Interventions
DRUGBI 695502
BI 695502 single i.v. infusion
DRUGbevacizumab
bevacizumab single i.v. infusion
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE
Eligibility
Sex/Gender
MALE
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males. 2. Complete medical history, including physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests. 3. Aged 21 to 50 years. 4. Body mass index below or equal to 30. 5. Body weight 65 to 95 kg, inclusive.
Exclusion criteria
1. Any finding of the medical examination (including blood pressure, pulse rate and ECG) deviating from normal and of clinical relevance. 2. Any evidence of a clinically relevant concomitant disease, as judged by the investigator. 3. History of relevant orthostatic hypotension, fainting spells, or blackouts. 4. Chronic or relevant acute infections. 5. History of relevant allergy/hypersensitivity (including allergy to the study medications or its excipients). 6. Intake of prescribed or over-the-counter drugs within less than 6 half-lives of the respective drug prior to study drug administration or during the trial. 7. Participation in another trial with a study medication within two months prior to administration or during the trial (six half-lives). 8. Smoker (\> 10 cigarettes or \> 3 cigars or \> 3 pipes/day). 9. Inability to refrain from smoking during days of confinement at the study center. 10. Current alcohol abuse as judged by the investigator. 11. Current drug abuse, as judged by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | Pharmacokinetic samples were collected predose, just before the end of the infusion, 2, 4, and 8 hours after the start of the infusion | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented as adjusted geometric mean (gMean) and geometric coefficient of variation (%) (gCV%). Adjustment were made for treatment effect and weight. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz) | Pharmacokinetic samples were collected predose, just before the end of the infusion, 2, 4, and 8 hours after the start of the infusion | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point is presented as adjusted geometric mean (gMean) and geometric coefficient of variation (%) (gCV%). Adjustment was made for treatment effect and weight. |
| Maximum Measured Concentration of the Analyte in Plasma (Cmax) | Pharmacokinetic samples were collected predose, just before the end of the infusion, 2, 4, and 8 hours after the start of the infusion. | Maximum measured concentration of the analyte in plasma (Cmax) is presented as adjusted geometric mean (gMean) and geometric coefficient of variation (%) (gCV%). Adjustment was made for treatment effect and weight. |
Countries
New Zealand
Participant flow
Recruitment details
This was a randomized, single-blind, single-dose, parallel-arm, active comparator, Phase I clinical trial. The trial was planned to be conducted in two stages and subjects were to be randomly allocated in each stage. Based on the interim analysis finalized on 18 February 2013, the trial was closed after Stage 1, and Stage 2 was not conducted.
Pre-assignment details
Subjects were randomized in a 1:1:1 ratio to receive BI 695502, United States (US)-licensed Avastin® or European Union (EU)-approved Avastin®.
Participants by arm
| Arm | Count |
|---|---|
| BI 695502 (T) Subjects were administered a single dose of 25 milligram per millilitre (mg/mL) BI 695502 concentrate for solution for infusion. | 30 |
| United States (US)-Licensed Avastin® (R1) Subjects were administered a single dose of 25 milligram per millilitre (mg/mL) US-licensed Avastin® solution for intravenous infusion. | 30 |
| European Union (EU)-Approved Avastin® (R2) Subjects were administered a single dose of 25 microgram per millilitre (mg/mL) EU-approved Avastin® concentrate for solution for infusion. | 31 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Other Reason | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | BI 695502 (T) | United States (US)-Licensed Avastin® (R1) | European Union (EU)-Approved Avastin® (R2) |
|---|---|---|---|---|
| Age, Continuous | 27.4 Years STANDARD_DEVIATION 6.7 | 26.8 Years STANDARD_DEVIATION 6.5 | 28.8 Years STANDARD_DEVIATION 8.1 | 26.6 Years STANDARD_DEVIATION 5.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 4 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 2 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 67 Participants | 23 Participants | 22 Participants | 22 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 91 Participants | 30 Participants | 30 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 | 0 / 31 |
| other Total, other adverse events | 25 / 30 | 19 / 30 | 21 / 31 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 31 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞).
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented as adjusted geometric mean (gMean) and geometric coefficient of variation (%) (gCV%). Adjustment were made for treatment effect and weight.
Time frame: Pharmacokinetic samples were collected predose, just before the end of the infusion, 2, 4, and 8 hours after the start of the infusion
Population: Pharmacokinetic (PK) set: The PK set included all subjects in the treated set (subjects who received at least one administration of trial medication) who provided at least one evaluable observation of a PK endpoint and had no important protocol violations relevant to the evaluation of PK biosimilarity.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695502 (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 7013.010 microgram*hour/milliliter | Geometric Coefficient of Variation 19.52 |
| United States (US)-Licensed Avastin® (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 7261.119 microgram*hour/milliliter | Geometric Coefficient of Variation 15.57 |
| European Union (EU)-Approved Avastin® (R2) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 7649.491 microgram*hour/milliliter | Geometric Coefficient of Variation 18.29 |
93.93% CI: [88.54, 105.35]ANOVA
93.93% CI: [83.5, 100.65]ANOVA
93.93% CI: [87.14, 103.4]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point is presented as adjusted geometric mean (gMean) and geometric coefficient of variation (%) (gCV%). Adjustment was made for treatment effect and weight.
Time frame: Pharmacokinetic samples were collected predose, just before the end of the infusion, 2, 4, and 8 hours after the start of the infusion
Population: Pharmacokinetic (PK) set: The PK set included all subjects in the treated set (subjects who received at least one administration of trial medication) who provided at least one evaluable observation of a PK endpoint and had no important protocol violations relevant to the evaluation of PK biosimilarity.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695502 (T) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz) | 6570.047 microgram*hour/milliliter | Geometric Coefficient of Variation 20.68 |
| United States (US)-Licensed Avastin® (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz) | 6639.315 microgram*hour/milliliter | Geometric Coefficient of Variation 18.46 |
| European Union (EU)-Approved Avastin® (R2) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz) | 7167.313 microgram*hour/milliliter | Geometric Coefficient of Variation 19.72 |
90% CI: [90.97, 107.64]ANOVA
90% CI: [84.02, 100.01]ANOVA
90% CI: [85.18, 100.74]ANOVA
Secondary
Maximum Measured Concentration of the Analyte in Plasma (Cmax)
Maximum measured concentration of the analyte in plasma (Cmax) is presented as adjusted geometric mean (gMean) and geometric coefficient of variation (%) (gCV%). Adjustment was made for treatment effect and weight.
Time frame: Pharmacokinetic samples were collected predose, just before the end of the infusion, 2, 4, and 8 hours after the start of the infusion.
Population: Pharmacokinetic (PK) set: The PK set included all subjects in the treated set (subjects who received at least one administration of trial medication) who provided at least one evaluable observation of a PK endpoint and had no important protocol violations relevant to the evaluation of PK biosimilarity.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 695502 (T) | Maximum Measured Concentration of the Analyte in Plasma (Cmax) | 23.783 microgram/milliliter | Geometric Coefficient of Variation 16.11 |
| United States (US)-Licensed Avastin® (R1) | Maximum Measured Concentration of the Analyte in Plasma (Cmax) | 23.425 microgram/milliliter | Geometric Coefficient of Variation 25.15 |
| European Union (EU)-Approved Avastin® (R2) | Maximum Measured Concentration of the Analyte in Plasma (Cmax) | 25.505 microgram/milliliter | Geometric Coefficient of Variation 15.18 |
90% CI: [92.74, 111.14]ANOVA
90% CI: [87.12, 99.81]ANOVA
90% CI: [83.91, 100.54]ANOVA