Ultrasound to Enhance Paclitaxel Uptake in Critical Limb Ischemia: the PACUS Trial

Study Overview
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Brief Summary
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The PACUS Trial was a single center, single blinded, randomized trial designed to evaluate the safety and efficacy of intravascular percutaneous catheter-delivered ultrasound energy to improve local Paclitaxel delivery effects in critical limb ischemia patients due to femoral-popliteal artery disease.

Detailed Description
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Study design The PACUS Trial was a single center, single blinded, randomized trial designed to evaluate the safety and efficacy of intravascular percutaneous catheter-delivered high intensity, low-frequency ultrasound utilizing CardioProlific Genesis™ System to improve local paclitaxel delivery effect in patients with CLI due to femoral-popliteal calcific lesions and occlusions. The protocol was approved by a Local Review Boards and the Institutional Ethics Committee. All patients provided written informed consent before enrollment. The trial was conducted in accordance with the declaration of Helsinki. Randomization Randomization occurred after successful crossing and pre-dilatation of the target lesion with a standard percutaneous angioplasty balloon without sub-intimal approach and/or flow limiting dissections. Patients were enrolled when a successful angiographic control was performed after PTA pre-dilatation. Subjects were randomly assigned by a computer-generated random sequence (2 blocks in a 1:1 ratio). Randomization was done in advance for all patients and without any stratification. The patients and physicians involved in the follow-up control were blinded to the treatment assignments through the completion of all 6 month follow-up evaluation. Operators were not blinded due to differences in treatment protocol. Twenty eight (28) patients were treated with an intravascular percutaneous catheter-delivered high intensity, low-frequency ultrasound and local Paclitaxel delivery with temporarily blood flow occlusion created by distal occlusion balloon (Study Group), and twenty eight (28) patients were treated with drug eluting balloon with conventional method (Control Group).

Official Title
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Use of Local Ultrasound to Enhance Local Paclitaxel Delivery Effect After Femoro-popliteal Percutaneous Transluminal Angioplasty in Patients With Critical Limb Ischemia: the PACUS Trial

Conditions
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Peripheral Arterial Disease, Angioplasty

Intervention / Treatment
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* Device: Local exposition of target lesion to high intensity, low-frequency ultrasound
* Device: drug eluting ballon angioplasty
* Device: Flow occlusion with an angioplasty balloon
* Drug: Local Paclitaxel infusion
* Procedure: Angiographic control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rutherford category ≥4 femoral-popliteal lesion ≥10cm successful intraluminal recanalization without need of a stent to obtain a satisfactory angiographic result at least one patent below the knee vessel patients older than 18 years Exclusion Criteria: Rutherford category < 4 pregnancy known allergies to study medications and materials need of sub-intimal approach to perform the recanalization target vessel stent release

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>After crossing the lesion with a guidewire, patients will be treated with intravascular high intensity, low-frequency ultrasound followed by local administration of liquid mixture of Paclitaxel and Iopromide-370 with predetermined dosage of 1.0 µg/mm | Device: Local exposition of target lesion to high intensity, low-frequency ultrasound<br>* Target lesion was exposed to 60 seconds of high intensity, low-frequency ultrasound generated by the Genesis™ system ( CardioProlific Inc., Hayward, CA). The ultrasound catheter is removed after the exposition.<br>Device: Flow occlusion with an angioplasty balloon<br>* Inflation of a 2 cm long balloon catheter Admiral (Medtronic) , located distally to the treatment area, in order to obtain a flow cessation<br>Drug: Local Paclitaxel infusion<br>* Paclitaxel in a mixture with contrast medium at 1.0 µg/mm³ concentration was delivered to the treatment area for 60 seconds. The column of the Paclitaxel mixture filling the vessel was observed under the fluoroscopy and sustained during 60 seconds. The Paclitaxel /contrast medium mixture was then aspired with a 50 cc syringe and the distal balloon was deflated.<br>Procedure: Angiographic control<br>* A final angiographic control was performed with injection of 10 cc of contrast medium and compared with the pre-procedural one.<br>|
| Active Comparator: Control group<br>After crossing the lesion with a guidewire, patients will be treated with drug eluting ballon angioplasty with the In.Pact Admiral ballon (Medtronic) | Device: drug eluting ballon angioplasty<br>* Target lesion was treated with an angioplasty, performed using the INPACT Admiral drug eluting ballon (Medtronic)<br>Procedure: Angiographic control<br>* A final angiographic control was performed with injection of 10 cc of contrast medium and compared with the pre-procedural one.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Freedom from clinically driven target lesion revascularization (TLR) and significant restenosis | Freedom from clinically driven target lesion revascularization (TLR) and significant restenosis as determined by digital subtraction angiography at 6 months follow-up | 6 months follow up | 
| Number of device and procedure related deaths and major adverse clinical events | Number of device and procedure related death and major adverse clinical events defined as stroke, myocardial infarction, need of surgical revascularization, distal embolization, recurrence of critical limb ischemia. | 1 months follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Intraoperative Technical success | Percentage of Technical success (Patients with technical success/Total population) was defined as successful recanalization of the target vessel with ≤30% residual stenosis after the procedure | Intraoperative | 
| Number of participants with Clinically driven target lesion revascularization | Number of participants with Target lesion revascularization, defined as any repeat surgical or percutaneous interventions of the target lesion due to loss of patency as evaluated by DSA | 12 months follow up | 
| Number of participants with clinical improvement | Number of participants with Clinical improvement, defined as freedom from target limb amputation, target vessel revascularization, and increase in Rutherford class. | 12 months follow up | 
| Number of Death and major adverse clinical events | Number of death and major adverse clinical events included stroke, myocardial infarction, need of surgical revascularization, distal embolization, recurrence of critical limb ischemia. | 12 months follow up |