A Study of Intra-thrombus Plasmin (Human) In Acute Peripheral Arterial Occlusion

Study Overview
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Brief Summary
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The primary purpose of this Phase 2 study is to optimize Plasmin delivery by comparing different delivery regimens in patients with peripheral arterial occlusion. The study includes a blinded plasminogen activator treatment group and a blinded plasminogen activator placebo group. The study will also assess safety and tolerability of Plasmin at 150 and 250 mg doses.

Official Title
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A Phase 2, Randomized, Open-label (With Blinded Plasminogen Activator and Placebo Control Groups) Study to Evaluate the Effects of Different Intra-thrombus Infusion Regimens of Plasmin (Human) Compared to Plasminogen Activator and Placebo In Patients With Acute Lower Extremity Native Artery or Bypass Graft Occlusion

Conditions
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Acute Peripheral Arterial Occlusion

Intervention / Treatment
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* Biological: Plasmin
* Biological: Plasminogen Activator
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unilateral limb ischemia - Society of Vascular Surgery Categories I and IIa Onset of symptoms less than or equal to 14 days Thrombosed infrainguinal bypass graft or native artery Diagnosis by arteriography of occlusive thrombus in graft or artery Ability to embed the infusion catheter into the thrombus Women of childbearing potential must use contraception and have a negative pregnancy test Exclusion Criteria: Any medical or social condition that may interfere with study participation Women who are pregnant or lactating Hemorrhagic stroke history Thrombotic or embolic stroke or cerebrovascular events (including transient ischemic attack) within one year Intracranial or spinal neurosurgery, or severe intracranial trauma in the last 3 months Major surgery, organ biopsy, or major trauma within the past 10 days Lumbar puncture or non-compressible arterial puncture in the past 10 days Intraocular surgery within the past 10 days Active gastrointestinal or organ bleeding Uncontrolled arterial hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) Known intracranial neoplasm, aneurysm, or arteriovenous malformation Current bleeding diathesis Platelet count <75 x 10e9/L Active graft infection Occlusion occurred within one month of synthetic graft placement Occlusion occurred within 6 months of autologous graft placement A sequential composite graft with dual outflows to correct multiple occlusions Medically unable to tolerate an open vascular procedure Known prothrombotic state Hemoglobin <10.0 g/dL Impaired renal function or renal disease that constitutes a contraindication to contrast angiography, including creatinine >2.0 mg/dL Treatment with a full dose plasminogen activator (PA) within the last 48 hours Treatment with a glycoprotein IIb/IIIa class of platelet inhibitor within the past 5 days Treatment with oral anticoagulants, and with an international normalized ratio of >1.7

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasmin Open-label Treatment Group A<br>Open-label 150 mg Plasmin administered without initial proximal pulse; 5-hour infusion using 10 mL/hour infusion rate. | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group B<br>Open-label 150 mg Plasmin administered with initial proximal pulse; 5-hour infusion using 15 mL/hour infusion rate | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group C<br>Open-label 150 mg Plasmin administered with proximal pulse; 5 hour infusion using 30 mL/hour infusion rate. | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group D<br>Open-label 150 mg Plasmin administered with proximal pulse; 2-hour infusion using 35 mL/hour infusion rate | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Active Comparator: Plasminogen Activator Blinded Group E<br>PA administered for five hours at a dose and volume according to the Investigator's clinical judgement/standard practice | Biological: Plasminogen Activator<br>* Plasminogen activator used according to the Investigator's clinical judgment.<br>* Other names: urokinase (UK);|
| Placebo Comparator: PA Placebo Blinded Treatment Arm F<br>PA placebo (normal saline for injection) administered for five hours at a dose and volume according to the Investigator's clinical judgement/standard practice for PA administration | Other: Placebo<br>* Normal saline for injection at the same volume as the plasminogen activator.<br>* Other names: Normal saline;|
| Experimental: Plasmin Open-label Treatment Group G<br>Open-label 150 mg Plasmin administered without pulsing; 5-hour infusion using 60 mL/hour infusion rate | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group H<br>Open-label 150 mg Plasmin administered without pulsing; 2-hour infusion using 75 mL/hour infusion rate | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group I<br>Open-label 150 mg Plasmin administered without pulsing; 5-hour infusion using 30 mL/hour infusion rate with balloon occlusion catheter | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group J<br>Open-label 150 mg Plasmin administered without pulsing; 2-hour infusion using 35 mL/hour infusion rate with balloon occlusion catheter | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|
| Experimental: Plasmin Open-label Treatment Group M<br>Open-label 250 mg Plasmin administered without pulsing; 5-hour infusion using 30 mL/hour infusion rate with balloon occlusion catheter | Biological: Plasmin<br>* Plasmin prepared in 0.9% saline for injection<br>* Other names: Plasmin (Human);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Subjects With >50% Thrombolysis | The proportion of subjects with >50% thrombolysis at the end of treatment compared to baseline by arteriography. | 5 hours (Treatment Groups A, B, C, G, I, M) or 2 hours (Treatment Groups D, H, J) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence of Major and Minor Bleeding Events, Deaths, Adverse Events, Serious Adverse Events, and Abnormal Laboratory Values as a Measure of Safety and Tolerability. | The incidence of major and minor bleeding events, deaths, adverse events, serious adverse events, and abnormal laboratory values as a measure of safety and tolerability. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Limb Ischemia