A Dose Escalation and Safety Study of Plasmin (Human) In Acute Lower Extremity Native Artery or Bypass Graft Occlusion

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of increasing doses of intra-thrombus Plasmin (Human) in acute peripheral arterial occlusion (aPAO). The ability of these Plasmin doses to dissolve the clots will be estimated by arteriography.

Detailed Description
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There is an unmet need for proven thrombolytic agent in acute peripheral arterial occlusion (aPAO). The current assortment of plasminogen activators are slow to dissolve clots in the leg, and may lead to bleeding complications. Plasmin is a direct thrombolytic that may act more quickly when infused directly into the clot and thus assist in restoring blood flow to the leg. There is a large reserve in blood alpha-2 antiplasmin in the blood to rapidly inactivate Plasmin outside of the clot. Plasmin has the potential for an improved bleeding risk profile in aPAO.

Official Title
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A Sequential Phase I/II Dose Escalation and Dose Selection Safety Study of Regional Intra-thrombus Plasmin (Human) Infusion In Acute Lower Extremity Native Artery or Bypass Graft Occlusion

Conditions
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Arterial Occlusive Diseases

Intervention / Treatment
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* Biological: Plasmin (Human) 25 mg
* Biological: Plasmin (Human) 50 mg
* Biological: Plasmin (Human) 75 mg
* Biological: Plasmin (Human) 100 mg
* Biological: Plasmin (Human) 125 mg
* Biological: Plasmin (Human) 150 mg
* Biological: Plasmin (Human) 175 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Women of childbearing potential must use adequate contraception for the duration of the study and must have a negative pregnancy test prior to study entry. Unilateral limb ischemia: SVS acute ischemia Category I or IIa. Onset of symptoms </= 14 days. Thrombosed (non-embolic) infrainguinal graft (synthetic, autologous, or single outflow composite) or infrainguinal native artery. For native arteries, only occlusions of ≥ 10 cm in length are eligible. Diagnosis of occlusive thrombus in the graft or artery by arteriography after Informed Consent is obtained. Ability to traverse the thrombus with a guidewire. Signed informed consent prior to study entry. Exclusion Criteria: Clinical evidence of significant disease that may interfere with the patient successfully completing the trial. Women who are pregnant or lactating, or first 10 days post-partum. Previous hemorrhagic stroke at any time. Thrombotic or embolic stroke or cerebrovascular events (including transient ischemic attack (TIA)) within one year. Intracranial or spinal neuro-surgery, or severe intracranial trauma in the last 3 months. Major surgery, organ biopsy, or major trauma within the last 10 days. Lumbar puncture or non-compressible arterial puncture in the last 10 days. Intra-ocular surgery within the last 10 days. Current bleeding diathesis. Active gastrointestinal or organ bleeding. Minor bleeding such as normal menses, cystitis, or minor hemorrhoidal bleeding are not exclusions. Uncontrolled arterial hypertension, defined as a systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg. Known intracranial neoplasm, aneurysm, or arterio-venous malformation. Platelet count < 75 x 10e9/L. Occlusion of a graft within 6 months of placement. Medically unable to tolerate an open vascular procedure. Known prothrombotic condition. Hemoglobin <10.0 g/dL Impaired renal function or renal disease that constitutes a contraindication to contrast angiography, including creatinine > 2.0 mg/dL or subjects on renal dialysis. Treatment with a glycoprotein IIb/IIIa class of platelet inhibitor within the past 5 days, for example, abciximab (ReoPro®), eptifibatide (Integrilin®) or tirofiban (Aggrastat®). Treatment with warfarin (Coumadin®) and with an INR of >1.7 (elevated INR at screening may be corrected prior to study enrollment.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasmin (Human) 25 mg<br>Plasmin (Human) 25 mg | Biological: Plasmin (Human) 25 mg<br>* Plasmin (Human) 25 mg delivered via an infusion catheter into the thrombus over approximately 5 hours.<br>* Other names: BAY-57-9602;|
| Experimental: Plasmin (Human) 50 mg<br>Plasmin (Human ) 50 mg | Biological: Plasmin (Human) 50 mg<br>* Plasmin (Human) 50 mg delivered via an infusion catheter into the thrombus over approximately 5 hours.<br>* Other names: BAY-57-9602;|
| Experimental: Plasmin (Human) 75 mg<br>Plasmin (Human) 75 mg | Biological: Plasmin (Human) 75 mg<br>* Plasmin (Human) 75 mg delivered via an infusion catheter into the thrombus over approximately 5 hours.<br>* Other names: BAY-57-9602;|
| Experimental: Plasmin (Human) 100 mg<br>Plasmin (Human) 100 mg | Biological: Plasmin (Human) 100 mg<br>* Plasmin (Human) 100 mg<br>* Other names: BAY-57-9602;|
| Experimental: Plasmin (Human) 125 mg<br>Plasmin (Human) 125 mg | Biological: Plasmin (Human) 125 mg<br>* Plasmin (Human) 125 mg delivered via an infusion catheter into the thrombus over approximately 5 hours.<br>* Other names: BAY-57-9602;|
| Experimental: Plasmin (Human) 150 mg<br>Plasmin (Human) 150 mg | Biological: Plasmin (Human) 150 mg<br>* Plasmin (Human) 150 mg delivered via an infusion catheter into the thrombus over approximately 5 hours.<br>* Other names: BAY-57-9602;|
| Experimental: Plasmin (Human) 175 mg<br>Plasmin (Human) 175 mg | Biological: Plasmin (Human) 175 mg<br>* Plasmin (Human) 175 mg delivered via an infusion catheter into the thrombus over approximately 5 hours.<br>* Other names: BAY-57-9602;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombolysis | Thrombolysis at the end of treatment compared to baseline by arteriography | Approximately 5 hours after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombolysis | Thrombolysis at 120 minutes compared to baseline by arteriography | Approximately 2 hours after start of treatment | 
| Avoidance of open surgical procedures | Percent of subjects at Day 30 who avoid open surgical procedures | 30 days | 
| Avoidance of amputation | Percent of subjects at Day 30 who avoid amputation | 30 days | 
| Avoidance of additional catheter-directed thrombolysis with a plasminogen activator or mechanical device thrombectomy | Percent of subjects at Day 30 who avoided additional catheter-directed thrombolysis with a plasminogen activator or mechanical device thrombectomy. | 30 days | 
| Avoidance of both open surgical procedures and additional thrombolysis with a plasminogen activator or mechanical device thrombectomy. | Percent of subjects at Day 30 who avoided both open surgical procedures and additional thrombolysis with a plasminogen activator or mechanical device thrombectomy. | 30 days | 
| Physiologic reperfusion defined as improvement in ankle brachial index (ABI) | Physiologic reperfusion defined as improvement in ABI (increase of ≥ 0.15) determined at the end of treatment, post intervention procedures, Day 1 to 2, Day 7, and Day 30. | End of treatment, post intervention procedures, Day 1 to 2, Day 7, and Day 30 | 
| Patency assessed by duplex ultrasound imaging | Patency assessed by duplex ultrasound imaging on the affected leg on Day 7 and Day 30 | Day 7 and Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thrombolytic, thrombolysis, acute peripheral arterial occlusion, peripheral vascular disease, thrombosis, endovascular