Healthy
Conditions
Brief summary
To establish the bioequivalence of alteplase derived from two different manufacturing processes.
Interventions
DRUGAlteplase (from modified manufacturing process)
Alteplase, TPA-05
DRUGAlteplase (from current manufacturing process)
Alteplase, TPA-02
DRUGHeparin-Natrium-5000-ratiopharm (unfractionated heparin)
Heparin-Natrium-5000-ratiopharm (unfractionated heparin)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part A: Open label Part B: Adaptive two-stage group-sequential design
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 45 years (inclusive) * Body mass index (weight divided by height squared) (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * Body weight of 65 - 100 kg (inclusive) at screening * Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance, e.g. thrombotic predisposition according to thrombophilic testing * Any evidence of a concomitant disease assessed as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity * During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 infection Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion. | The area under the concentration-time curve of alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. |
| Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion. | The area under the concentration-time curve of Alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. |
| Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax) | Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion. | Maximum measured concentration of alteplase in plasma is reported. |
| Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax) | Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion. | Maximum measured concentration of Alteplase in plasma (Cmax) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion. | Area under the concentration-time curve of alteplase in plasma over interval from 0 extrapolated to infinity is reported. |
| Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion. | Area under the concentration-time curve of alteplase in plasma over the interval from 0 extrapolated to infinity is reported. |
Countries
Germany
Participant flow
Recruitment details
This was a randomised, open-label, 2 -way cross-over design with at least 24 h wash-out, to establish the bioequivalence of alteplase derived from two different manufacturing processes (new process, tissue plasminogen activator (TPA)-05, vs. current process, TPA-02) in healthy male volunteers.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. In this cross-over trial 2 single doses of alteplase were infused on 2 consecutive days keeping a wash-out period of at least 24 h.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Alteplase, TPA-02 Then Alteplase, TPA-05 Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 min infusion.
The 2 treatment periods were separated by a washout period of at least 24 hours (h). | 6 |
| Part A: Alteplase, TPA-05 Then Alteplase, TPA-02 Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 min infusion.
The 2 treatment periods were separated by a washout period of at least 24 hours (h). | 6 |
| Part B: Alteplase, TPA-02 Then Alteplase, TPA-05 Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 min infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.
The 2 treatment periods were separated by a washout period of at least 24 hours (h). | 9 |
| Part B: Alteplase, TPA-05 Then Alteplase, TPA-02 Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 min infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.
The 2 treatment periods were separated by a washout period of at least 24 hours (h). | 9 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Wash-out After Period 1 | Adverse Event | 1 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Part B: Alteplase, TPA-02 Then Alteplase, TPA-05 | Part B: Alteplase, TPA-05 Then Alteplase, TPA-02 | Total | Part A: Alteplase, TPA-05 Then Alteplase, TPA-02 | Part A: Alteplase, TPA-02 Then Alteplase, TPA-05 |
|---|---|---|---|---|---|
| Age, Continuous | 31.7 Years STANDARD_DEVIATION 5.8 | 35.8 Years STANDARD_DEVIATION 5.8 | 33.5 Years STANDARD_DEVIATION 5.8 | 32.2 Years STANDARD_DEVIATION 6.2 | 34.3 Years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 8 Participants | 29 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 8 Participants | 29 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 30 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 18 | 0 / 11 | 0 / 17 |
| other Total, other adverse events | 1 / 10 | 7 / 18 | 4 / 11 | 6 / 17 |
| serious Total, serious adverse events | 0 / 10 | 0 / 18 | 0 / 11 | 0 / 17 |
Outcome results
Primary
Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)
The area under the concentration-time curve of alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.
Time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
Population: Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.
Primary
Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax)
Maximum measured concentration of alteplase in plasma is reported.
Time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
Population: Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.
Primary
Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)
The area under the concentration-time curve of Alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.
Time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
Population: Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Alteplase, TPA -02 | Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz) | 369.21 hour * nanogram / milliliter (h*ng/mL) |
| Part A: Alteplase, TPA-05 | Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz) | 377.35 hour * nanogram / milliliter (h*ng/mL) |
Comparison: The null hypothesis was that the ratio of expected geometric least squares means Alteplase, TPA-02 vs. Alteplase, TPA-05 is less than 80.00% or more than 125.00%.~The statistical model used for the analysis of this endpoints was an analysis of variance (ANOVA) model on the logarithmic scale.~This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. All effects were considered as fixed.92.83% CI: [94.87, 110.1]
Primary
Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax)
Maximum measured concentration of Alteplase in plasma (Cmax) is reported.
Time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
Population: Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Alteplase, TPA -02 | Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax) | 738.35 nanogram / milliliter (ng/mL) |
| Part A: Alteplase, TPA-05 | Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax) | 781.24 nanogram / milliliter (ng/mL) |
Comparison: The null hypothesis was that the ratio of expected geometric least squares means Alteplase, TPA-02 vs. Alteplase, TPA-05 is less than 80.00% or more than 125.00%.~The statistical model used for the analysis of this endpoints was an analysis of variance (ANOVA) model on the logarithmic scale.~This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. All effects were considered as fixed.92.83% CI: [99.18, 112.88]
Secondary
Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of alteplase in plasma over interval from 0 extrapolated to infinity is reported.
Time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
Population: Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.
Secondary
Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of alteplase in plasma over the interval from 0 extrapolated to infinity is reported.
Time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
Population: Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Alteplase, TPA -02 | Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞) | 371.85 hour*nanogram/milliliter (h*ng/mL) |
| Part A: Alteplase, TPA-05 | Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞) | 379.90 hour*nanogram/milliliter (h*ng/mL) |
Comparison: The null hypothesis was that the ratio of expected geometric least squares means Alteplase, TPA-02 vs. Alteplase, TPA-05 is less than 80.00% or more than 125.00%.~The statistical model used for the analysis of this endpoints was an analysis of variance (ANOVA) model on the logarithmic scale.~This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. All effects were considered as fixed.92.83% CI: [94.79, 110.12]