Treatment of Chronic Deep Vein Thrombosis (DVT) and Post-Thrombotic Syndrome (PTS) With the EkoSonic® Endovascular System

Study Overview
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Brief Summary
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To evaluate the efficacy of ultrasound accelerated thrombolysis using the EkoSonic® Endovascular System with standard infusion of thrombolytic drug for post-thrombotic syndrome from chronic venous occlusion.

Detailed Description
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The study is designed to evaluate the safety and efficacy of ultrasound accelerated thrombolysis using the EkoSonic® Endovascular System with standard infusion of a thrombolytic drug for PTS and chronic DVT. Clinical effectiveness will be evaluated using a standard measure of severity of post-thrombotic syndrome over a year.

Official Title
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ACCElerated ThrombolySiS for Post-Thrombotic Syndrome Using the EKOS System

Conditions
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Deep Vein Thrombosis, Post-thrombotic Syndrome

Intervention / Treatment
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* Device: EkoSonic® Endovascular System
* Biological: Alteplase


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Male or female greater than or equal to (≥) 18 years of age and less than or equal to (≤) 75 years of age. Proximal DVT (iliac vein, common femoral vein, deep femoral vein, and femoral vein) that was objectively diagnosed with duplex imaging and/or venography ≥ 6 months prior to study screening. Persistent chronic DVT causing restrictive flow, as confirmed by imaging, within 60 days prior to the study procedure. Villalta score ≥8 for the affected limb within 30 days prior to the study procedure. Failed a minimum of 3 consecutive months of conservative treatment (therapeutic anticoagulation and compression stockings) according to the completed Adherence to Conservative Treatment Form. Key Exclusion Criteria: Treated with mechanical thrombectomy within 2 weeks of the study thrombolysis procedure. Treated with thrombolysis drugs within 48 hours of the study thrombolytic procedure. Life expectancy less than (<) 1 year. Body Mass Index (BMI) greater than (>) 40 kilograms/square meter (kg/m^2) or per Investigator's discretion participant is able tolerate the procedure and be compliant with post-procedure increased physical activity. No flow in popliteal vein on duplex imaging Isolated iliac vein only thrombus. Thrombus extending ≥ 3 centimeters (cm) into the inferior vena cava (IVC). If central venous occlusion, consider computed tomography (CT) or magnetic resonance venography (MRV). For participants with bilateral DVT, it is recommended that central imaging be performed prior to treatment to evaluate the status of the IVC. Active bleeding, recent (<3 months) gastrointestinal (GI) bleeding, active peptic ulcer, severe liver dysfunction, and bleeding diathesis. Recent (<3 months) internal eye surgery or hemorrhagic retinopathy; recent (<10 days) major surgery, cataract surgery, trauma, cardiopulmonary resuscitation (CPR), obstetrical delivery, or other invasive procedure. History of stroke or intracranial/intraspinal bleed, tumor, vascular malformation, or aneurysm. Active cancer (metastatic, progressive, or treated within the last 6 months). Participants with non-melanoma primary skin cancers are eligible to participate in the study. Hemoglobin <9.0 milligrams/deciliter (mg/dL) within 24 hours prior to the procedure International normalized ratio (INR) ≥1.5 nanograms/deciliter (ng/dL) within 24 hours prior to the procedure. Platelet count <100,000 cells/cubic millimeter (cells/mm^3) or >700,000 cells/mm^3 within 24 hours prior to the procedure. Creatinine outside the normal range for the treating institution and considered clinically significant by the Investigator. Uncontrolled hypertension, defined as systolic >175 millimeters of mercury (mmHg) and a diastolic >110 mmHg. Use of clopidogrel, ticlopidine, or other thienopyridine antiplatelet drug within 7 days of the study procedure. In the judgment of the clinician, the participant is at high risk for catastrophic bleeding.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EkoSonic® Endovascular System<br>Thrombolytic infusion (Alteplase), at an infusion rate of 0.5-1.0 milligrams/hour (mg/hr) will be delivered to the participants with chronic lower extremity venous obstruction after DVT and PTS through the EkoSonic® Endovascular System for at least 12 hours and overnight as needed up to a maximum of 48 hrs. The alteplase dose could be adjusted per investigator discretion, but not to be exceeded 1 mg/hr or a total dose of 48 mg. | Device: EkoSonic® Endovascular System<br> <br> Biological: Alteplase<br>* Recombinant tissue plasminogen activator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Villalta Score at Day 30 Post-EkoSonic® Study Treatment Procedure | Clinical efficacy was evaluated using the Villalta score at Baseline compared to 30 days Post-EkoSonic® study treatment procedure. Villalta scale (post thrombotic syndrome score) is used for the assessment of symptoms and clinical signs. Participants rated the following symptoms for each leg: pain, cramps, heaviness, pruritus, and paresthesia on a scale ranging from 0 (not present/minimal) to 3 (severe). The study coordinator or nurse rated the following clinical signs in participants for each leg: pre-tibial edema, induration of the skin, hyperpigmentation, new venous extasia, redness during calf compression, and pain during calf compression on a scale ranging from 0 (not present/minimal) to 3 (severe). Total score ranged from 0 to 33. Higher scores represent more severe disease. | Baseline (within 30 days of treatment), Day 30 | 
| Percentage of Segments of Limbs That Achieved at Least 4-Point Reduction From Baseline in Villalta Score at Day 30 | Clinical efficacy was evaluated using the Villalta score at Baseline compared to 30 days Post-EkoSonic® study treatment procedure. Limbs with revascularization procedures were considered non-responders. Villalta scale (post thrombotic syndrome score) is used for the assessment of symptoms and clinical signs. Participants rated the following symptoms for each leg: pain, cramps, heaviness, pruritus, and paresthesia on a scale ranging from 0 (not present/minimal) to 3 (severe). The study coordinator or nurse rated the following clinical signs in participants for each leg: pre-tibial edema, induration of the skin, hyperpigmentation, new venous extasia, redness during calf compression, and pain during calf compression on a scale ranging from 0 (not present/minimal) to 3 (severe). Total score ranged from 0 to 33. Higher scores represent more severe disease. | Baseline (within 30 days of treatment), Day 30 | 
| Change From Baseline in Blood Flow (Calculated by Time to Washout in the Affected Segment) at Post-Adjunctive Therapy | Change in blood flow was calculated by time to washout in the affected segments in the participants. Time to femoral vein (FV) washout and external iliac vein (EIV) washout was reported. | Baseline (Within 30 days of treatment), Day 0 | 
| Number of Participants With Major Bleeding | Major bleeding was defined as: Fatal bleeding; and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome; and/or bleeding causing a fall in hemoglobin of ≥2.0 grams/deciliter (g/dL), or leading to transfusion of ≥2 units of whole blood or red blood cells. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | From start of study drug infusion up to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Ouriel Score (Venous Volumetric Index [VVI]) at Post-Adjunctive Therapy | The Ouriel score was designed to provide a more accurate quantitative estimate of the thrombus mass by calculating a volumetric index for all the venous segments. 10 venous segments were considered. Included segments were the inferior vena cava, common iliac veins, external iliac veins, internal iliac veins, common femoral veins, superficial and deep femoral veins, and popliteal veins and segments of the anterior tibial veins, posterior tibial veins, and peroneal veins. A normalized volumetric score was calculated for each segment by combining measurements from computed tomography, ultrasonography, and venography. Partially occluded veins were assigned a score of one-half the score value for the segment. The score varies from 1 for a single calf vein to 26 for the infrarenal inferior vena cava. The maximum score was 63 per limb. Higher score indicated worse disease prognoses. | Baseline (Within 30 days of treatment), Day 0 | 
| Number of Participants With at Least 5-Point Reduction From Baseline in Ouriel Score at Post-Adjunctive Therapy | The Ouriel score was designed to provide a more accurate quantitative estimate of the thrombus mass by calculating a volumetric index for all the venous segments. 14 venous segments were considered. Included segments were the inferior vena cava, common iliac veins, external iliac veins, internal iliac veins, common femoral veins, superficial femoral veins, deep femoral veins, and popliteal veins and segments of the anterior tibial veins, posterior tibial veins, and peroneal veins. A normalized volumetric score was calculated for each segment by combining measurements from computed tomography, ultrasonography, and venography. Partially occluded veins were assigned a score of one-half the score value for the segment. The score varies from 1 for a single calf vein to 26 for the infrarenal inferior vena cava. The maximum score was 63 per limb. Higher score indicated worse disease prognoses. | Baseline (Within 30 days of treatment), Day 0 | 
| Change From Baseline in Villalta Score at Days 90, 180, and 365 Post-EkoSonic® Study Treatment Procedure | Villalta scale (post thrombotic syndrome score) is used for the assessment of symptoms and clinical signs. Participants rated the following symptoms for each leg: pain, cramps, heaviness, pruritus, and paresthesia on a scale ranging from 0 (not present/minimal) to 3 (severe). The study coordinator or nurse rated the following clinical signs in participants for each leg: pre-tibial edema, induration of the skin, hyperpigmentation, new venous extasia, redness during calf compression, and pain during calf compression on a scale ranging from 0 (not present/minimal) to 3 (severe). Total score ranged from 0 to 33. Higher scores represent more severe disease. | Baseline (within 30 days of treatment), Days 90, 180, and 365 | 
| Percentage of Segments of Limbs That Achieved at Least 4-Point Reduction From Baseline in Villalta Score at Days 90, 180, and 365 | Limbs with revascularization procedures were considered non-responders. Villalta scale (post thrombotic syndrome score) is used for the assessment of symptoms and clinical signs. Participants rated the following symptoms for each leg: pain, cramps, heaviness, pruritus, and paresthesia on a scale ranging from 0 (not present/minimal) to 3 (severe). The study coordinator or nurse rated the following clinical signs in participants for each leg: pre-tibial edema, induration of the skin, hyperpigmentation, new venous extasia, redness during calf compression, and pain during calf compression on a scale ranging from 0 (not present/minimal) to 3 (severe). Total score ranged from 0 to 33. Higher scores represent more severe disease. | Baseline (within 30 days of treatment), Days 90, 180, and 365 | 
| Percentage of Treated Veins Segments of Limbs With Absence of Re-Occlusion, as Documented by Duplex Imaging | Absence of re-occlusion in following treated veins has been reported: common femoral vein (CFV), common iliac vein (CIV), distal femoral vein (FV), external iliac vein (EIV), popliteal vein, and proximal femoral vein (FV). | Day 365 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Sub-Scale Score and Physical Component Score (PCS) at Days, 30, 90, 180, and 365 | SF- 36 investigates the standard of quality of life through a general health assessment. It is a 36-item questionnaire measuring 8 domains (physical functioning [PF], role physical [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], role emotional [RE], and mental health [MH]). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. The PCS score summarizes the subscales physical functioning, role-physical, bodily pain, and general health. Total score range for PCS was 0 (lowest level of physical functioning) to 100 (highest level of physical functioning). | Baseline (within 30 days of treatment), Days 30, 90, 180, and 365 | 
| Number of Treated Limbs With Shift From Baseline in Clinical Stages (Symptomatic and Asymptomatic) of Clinical, Etiologic, Anatomic, Pathophysiological (CEAP) Classification at Days 30, 90, 180, and 365 | Status of clinical signs and symptoms of lower limb venous disease was measured by CEAP classification. The CEAP clinical Categories were as follows: C0- no visible or palpable signs of venous disease, C1- telangiectasies or reticular veins, C2- varicose veins, C3- edema, C4a- pigmentation and eczema, C4b- lipodermatosclerosis and atrophie blanche, C5- healed venous ulcer, and C6- active venous ulcer. C0 was of the least clinical concern and C6 was the worst stage. Each clinical class was further characterized by the (clinical stages) presence or absence of symptoms (ache, pain, tightness, skin irritation, heaviness, muscle cramps, as well as other complaints attributable to venous dysfunction): asymptomatic and symptomatic. | Baseline (within 30 days of treatment), Days 30, 90, 180, and 365 | 
| Change From Baseline in Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) Score At Days 30, 90, 180, and 360 | The VEINES-QOL/Sym is a participant-based questionnaire designed for self-completion and measures deep vein thrombosis (DVT) impact on symptoms and quality of life from the participants' perspective. It contains 26 items covering participant DVT: symptoms, limitations in daily activities, and psychological impact. A separate summary score VEINES-QOL ranges from 0 (worst quality of life) to 100 (best quality of life). Higher scores indicated a better quality of life. | Baseline (within 30 days of treatment), Days 30, 90, 180, and 365 | 
| Change From Baseline in Venous Clinical Severity Score (VCSS) in Study Leg at Days 30, 90, 180, and 365 | The VCSS system includes 10 clinical descriptions (pain, varicose veins, venous edema, skin pigmentation, inflammation, induration, number of active ulcers, duration of active ulceration, size of active ulceration, and level of compliance with medical compression therapy), scored from 0 to 3 (total possible score, 30) with 0 = absent, 1 = mild, 2 = moderate and 3 = severe. Total VCSS was the sum of all VCSS assessment scores from categories for a given time point. Total score ranged from 0 (absent) to 30 (severe). Lower values represent a better outcome, that is, a level of pain less than that experienced at baseline. | Baseline (within 30 days of treatment), Days 30, 90, 180, and 365 | 
| Number of Participants With PTS-induced Admission to an Emergency Room or Unplanned Visits to a Physician's Office or Hospitalization | Number of participants with PTS-induced admission to an emergency room or unplanned visits to a physician's office or hospitalization, are reported. A participant can have more than one PTS-induced health issue. | From the time of the EkoSonic® procedure (Day 0) up to 365 days | 
| Time From Starting Initial Thrombolytic Infusion to Discharge From the Hospital | This Outcome Measure was to measure the time that the participant's initial thrombolytic infusion started to the time the participant was discharged from the hospital. | From the time of the EkoSonic® procedure (Day 0) up to 365 days | 
| Number of Participants Who Had Symptomatic PE During Hospitalization for Study Procedure | Symptomatic PE was diagnosed using computed tomography pulmonary angiogram (CTPA), single positron emission computed tomography (SPECT), and ventilation-perfusion (VQ). | From starting the initial thrombolytic infusion (Day 0) through discharge from hospital (up to Day 38) | 
| Number of Participants Who Died Due to Any Cause | Number of participants who died due to any cause for up to 365 days following the conclusion of the study procedure, were reported. | Baseline (within 30 days of treatment) up to Day 365 | 
| Number of Participants Who Had Adverse Events (AEs), Related (to the Study Procedure/Device/Medications) AEs, and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A summary of non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline (within 30 days of treatment) up to Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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deep vein thrombosis, post-thrombotic syndrome, chronic deep vein thrombosis