Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis

Study Overview
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Brief Summary
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The purpose of this study is to determine if the use of adjunctive Pharmacomechanical Catheter Directed Thrombolysis, which includes the intrathrombus administration of rt-PA--Activase (Alteplase),can prevent the post-thrombotic syndrome(PTS)in patients with symptomatic proximal deep vein thrombosis(DVT)as compared with optimal standard DVT therapy alone.

Detailed Description
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Activase, the study drug, is a fibrinolytic drug that is indicated for use in acute myocardial infarction, acute ischemic stroke, and acute massive pulmonary embolism in adults. Previous studies have established the ability of rt-PA to lyse venous thrombus in patients with deep vein thrombosis (DVT), and suggest that successful rt-PA mediated thrombolysis can prevent the post-thrombotic syndrome (PTS), a morbid, late complication of DVT that occurs in nearly 50% of patients. rt-PA is delivered directly into venous thrombus using a catheter/device which is embedded within the thrombus by a physician under imaging guidance. This method of rt-PA delivery, pharmacomechanical catheter-directed intrathrombus thrombolysis (PCDT),is thought to be safer, more effective, and more efficient than previous methods. The question of whether PCDT using rt-PA improves long-term DVT patient outcomes with acceptable risk and cost has not yet been addressed. The rationale for performing the ATTRACT Trial is based upon: the major burden of PTS on DVT patients and the U.S. healthcare system the association between rapid clot lysis and prevention of PTS the proven ability of rt-PA to dissolve venous thrombus in proximal DVT recent advances in CDT methods which may lower bleeding risk the major clinical controversy on whether CDT should be routinely used for first-line DVT therapy

Official Title
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Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis--The ATTRACT Trial

Conditions
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Deep Vein Thrombosis, Venous Thrombosis, Postphlebitic Syndrome, Venous Thromboembolism, Post Thrombotic Syndrome

Intervention / Treatment
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* Drug: Recombinant tissue plasminogen activator (rt-PA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptomatic proximal DVT involving the iliac, common femoral, and/or femoral vein. Exclusion Criteria: Age less than 16 years or greater than 75 years. Symptom duration > 14 days for the DVT episode in the index leg (i.e., non-acute DVT). In the index leg: established PTS, or previous symptomatic DVT within the last 2 years. In the contralateral (non-index) leg: symptomatic acute DVT a) involving the iliac and/or common femoral vein; or b) for which thrombolysis is planned as part of the initial therapy. Limb-threatening circulatory compromise. Pulmonary embolism with hemodynamic compromise (i.e., hypotension). Inability to tolerate PCDT procedure due to severe dyspnea or acute systemic illness. Allergy, hypersensitivity, or thrombocytopenia from heparin, rt-PA, or iodinated contrast, except for mild-moderate contrast allergies for which steroid pre-medication can be used. Hemoglobin < 9.0 mg/dl, INR > 1.6 before warfarin was started, or platelets < 100,000/ml. Moderate renal impairment in diabetic patients (estimated glomerular filtration rate [GFR] < 60 ml/min) or severe renal impairment in non-diabetic patients (estimated GFR < 30 ml/min). Active bleeding, recent (< 3 mo) GI bleeding, severe liver dysfunction, bleeding diathesis. Recent (< 3 mo) internal eye surgery or hemorrhagic retinopathy; recent (< 10 days) major surgery, cataract surgery, trauma, cardiopulmonary resuscitation, obstetrical delivery, or other invasive procedure. History of stroke or intracranial/intraspinal bleed, tumor, vascular malformation, aneurysm. Active cancer (metastatic, progressive, or treated within the last 6 months). Exception: patients with non-melanoma primary skin cancers are eligible to participate in the study. Severe hypertension on repeated readings (systolic > 180 mmHg or diastolic > 105 mmHg). Pregnant (positive pregnancy test, women of childbearing potential must be tested). Recently (< 1 mo) had thrombolysis or is participating in another investigational drug study. Use of a thienopyridine antiplatelet drug (except clopidogrel) in the last 5 days. Life expectancy < 2 years or chronic non-ambulatory status. Inability to provide informed consent or to comply with study assessments (e.g. due to cognitive impairment or geographic distance).

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 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: A-Intervention<br>PCDT with intrathrombus delivery of recombinant tissue plasminogen activator (rt-PA, maximum allowable total dose 35 mg) into the DVT over a period of up to 24 hours. Three methods of initial rt-PA delivery will be used: 1) Trellis-8 Peripheral Infusion System - maximum first-session rt-PA dose 25 mg; 2) AngioJet Rheolytic Thrombectomy System - maximum first-session rt-PA dose 25 mg; or 3) Catheter-directed rt-PA infusion for up to 24 hours at 0.01 mg/kg/hr (maximum 1.0 mg/hr) via a multisidehole infusion catheter. Before and after PCDT, patients will receive standard DVT therapy as in the Control Arm | Drug: Recombinant tissue plasminogen activator (rt-PA)<br>* Pharmacomechanical catheter-directed thrombolysis, consisting of intrathrombus administration of rt-PA using a catheter/device.<br>* Other names: Alteplase;|
| No Intervention: B-Control<br>Initial anticoagulant therapy with unfractionated heparin, enoxaparin, dalteparin, or tinzaparin, for at least 5 days, overlapped with long-term oral warfarin (target international normalized ratio 2.0 - 3.0). Elastic compression stockings will be prescribed | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Post-Thrombotic Syndrome (Villalta Scale) | Patients who experienced one of the following occurrences in the index leg between the 6 month and 24 month post-randomization follow-up visits, inclusive: 1) Villalta score of 5 or greater; 2) leg ulcer; or 3) late endovascular procedure performed to treat severe venous disease. The Villalta scale ranges from 0-33 points, with higher scores being worse. | Between 6 and 24 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Non-post-thrombotic Syndrome Treatment Failure | A major non-post-thrombotic-syndrome treatment failure refers to when any of three events occurred in the index leg: 1) an unplanned endovascular procedure to treat severe venous symptoms within 6 months post-randomization; 2) venous gangrene within 6 months; or 3) an amputation within 24 months. | Through 24 months | 
| Any Treatment Failure | Composite of PTS and major non-PTS treatment failure | Through 24 months | 
| Moderate-to-severe Post-thrombotic Syndrome | Proportion of patients with Villalta score of 10 or higher at any time between the 6 month and 24 month follow-up visits, inclusive. The Villalta scale ranges from 0-33 points, with higher scores being worse. | Between 6 and 24 months after randomization | 
| Major Bleeding | Defined as clinically overt bleeding that is associated with a fall in the hemoglobin level of at least 2.0 g/dl, transfusion of ≥ 2 units of red blood cells, or involvement of a critical site (e.g. intracranial, intraspinal). | Within 10 days after randomization | 
| Major Bleeding | Defined as clinically overt bleeding that was associated with a fall in the hemoglobin level of at least 2.0 g/dl, transfusion of ≥ 2 units of red blood cells, or involvement of a critical site (e.g. intracranial, intraspinal). | Within 24 months after randomization | 
| Any (Minor + Major) Bleeding | Clinically overt bleeding that occurred through 10 days post-randomization | Within 10 days after randomization | 
| Any (Major + Minor) Bleeding | Clinically overt bleeding that occurred within 24 months post-randomization | Within 24 months after randomization | 
| Recurrent Venous Thromboembolism | Proportion of patients with symptomatic recurrent venous thromboembolism (including DVT and/or PE) | Within 10 days after randomization | 
| Recurrent Venous Thromboembolism | Symptomatic recurrent venous thromboembolism (DVT and/or PE) | Within 24 months after randomization | 
| Death | All-cause mortality | Within 10 days after randomization | 
| Death | All-cause mortality | Within 24 months after randomization | 
| Severity of Post-thrombotic Syndrome (Villalta) | Mean Villalta scale score at the specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse. | At 6 months | 
| Severity of Post-thrombotic Syndrome (Villalta) | Mean Villalta scale score at the specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse. | At 12 months | 
| Severity of Post-thrombotic Syndrome (Villalta) | Mean Villalta scale score at specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse. | At 18 months | 
| Severity of Post-thrombotic Syndrome (Villalta) | Mean Villalta scale score at specified follow-up visit. Villalta score ranges from 0-33 points, with higher scores being worse. | At 24 months | 
| Venous Clinical Severity Score | Mean Venous Clinical Severity Score (VCSS) at the specified follow-up visit; range 0-27 (did not use compression item), higher score is worse | At 6 months | 
| Venous Clinical Severity Score | Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item) | At 12 months | 
| Venous Clinical Severity Score | Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item) | At 18 months | 
| Venous Clinical Severity Score | Mean VCSS score at the specified follow-up visit; range 0-27 (did not use compression item) | At 24 months | 
| Change in General Quality of Life - Physical | Short-Form-36 Health Survey, Version 2, Physical Component Summary (PCS) Scale. Range of scores 0-100 with higher scores representing better quality of life. | Baseline to 24 months post-randomization | 
| Change in General Quality of Life - Mental | Short-Form-36 Health Survey, Version 2, Mental Component Summary (MCS) Scale. Range of scores 0-100 with higher scores representing better quality of life. | Baseline to 24 months post-randomization | 
| Change in Venous Disease-specific Quality of Life | Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) questionnaire. Range of scores 0-100 with higher scores representing better quality of life, and higher change scores representing greater improvement from baseline. | Baseline to 24 months post-randomization | 
| Change in Leg Pain Severity | Likert pain scale ranging from 1-7, with higher scores representing a greater intensity of pain | Baseline to 10 days post-randomization | 
| Change in Leg Pain Severity | Likert pain scale ranging from 1-7, with higher scores representing a greater intensity of pain | Baseline to 30 days post-randomization | 
| Change in Leg Circumference | Mean calf circumference measured 10 cm below the tibial tuberosity | Baseline to 10 days post-randomization | 
| Change in Leg Circumference | Mean calf circumference measured 10 cm below the tibial tuberosity | Baseline to 30 days post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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deep vein thrombosis, deep venous thrombosis, post thrombotic syndrome, blood clot, thrombolysis, tissue plasminogen activator, rt-PA, Activase, mechanical thrombectomy, pharmacomechanical, ATTRACT