A Study in Healthy Men to Compare 2 Different Formulations of Alteplase

Study Overview
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Brief Summary
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To establish the bioequivalence of alteplase derived from two different manufacturing processes.

Official Title
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Bioequivalence of Alteplase Derived From Two Different Manufacturing Processes Following Intravenous Administration in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Alteplase (from modified manufacturing process)
* Drug: Alteplase (from current manufacturing process)
* Drug: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Part A: Open label Part B: Adaptive two-stage group-sequential design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part B: Alteplase, TPA-02 then Alteplase, TPA-05<br> | Drug: Alteplase (from modified manufacturing process)<br>* Alteplase, TPA-05<br>Drug: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>* Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>|
| Active Comparator: Part B: Alteplase, TPA-05 then Alteplase, TPA-02<br> | Drug: Alteplase (from current manufacturing process)<br>* Alteplase, TPA-02<br>Drug: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>* Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>|
| Experimental: Part A: Alteplase, TPA-05 then Alteplase, TPA-02<br>Open-label | Drug: Alteplase (from modified manufacturing process)<br>* Alteplase, TPA-05<br>Drug: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>* Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>|
| Active Comparator: Part A: Alteplase, TPA-02 then Alteplase, TPA-05<br> | Drug: Alteplase (from current manufacturing process)<br>* Alteplase, TPA-02<br>Drug: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>* Heparin-Natrium-5000-ratiopharm (unfractionated heparin)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 
| Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax) | Maximum measured concentration of alteplase in plasma is reported. | 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. | 
| Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax) | Maximum measured concentration of Alteplase in plasma (Cmax) is reported. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. |