Intervention With Selution SLR™ Agent Balloon for Endovascular Latent Limus Therapy for Failing AV Fistulas (ISABELLA) Trial

Study Overview
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Brief Summary
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The most common problem with haemodialysis arteriovenous fistulas (AVF) and arterio-venous grafts (AVG) is stenosis, which can lead to inadequate dialysis, and eventual access thrombosis. Conventional plain old balloon angioplasty (CBA) is associated with high recurrence rates of stenosis and repeated interventions. The advent of successful drug-eluting technology in the treatment of the coronary vascular bed and subsequent positive accumulating evidence in the peripheral arterial circulation has prompted the use of drug coated balloons (DCB) in the access fistula circuit for venous stenosis and in-stent restenosis. Recent studies suggest that DCBs may significantly reduce re-intervention rates on native and recurrent lesions. The restenosis process is in part or in whole the result of neo-intimal hyperplasia (NIH) and NIH is considered the main culprit in access circuit target lesion stenosis. NIH is the blood vessel's healing response to the barotrauma from the angioplasty process. A critical component of NIH is the cellular proliferative stage with mononuclear leucocytes identified as the primary inflammatory cell type involved. The rationale for drug elution is to block the NIH response with an anti-metabolite such as paclitaxel. It is important to emphasize that the role of drug elution in the treatment of vascular stenosis is not to obtain a good haemodynamic and luminal result but to preserve a good result obtained during POBA from later restenosis due to NIH and minimise reinterventions and readmissions to hospital for what is a frail population of patients. A meta-analysis performed by Khawaja et al. seemed to suggest that DCBs conferred some benefit in terms of improving target lesion primary patency (TLPP) in AVFs. An updated meta-analysis performed by our own institution recently reinforced that DCB appears to be a better and safe alternative to CBA in treating patients with stenosis within all haemodialysis circuits (fistulas and grafts) based on 6- and 12-months primary patency and increased intervention free period 5. However, this was not reflected in the largest RCT to date of DCB vs CBA in AVF with no superior target lesion patency demonstrated at six months and one and two years follow-up. Another recent meta-analysis found paclitaxel-coated balloons (PCB) showed no statistically significant improvement over conventional balloons in decreasing fistula stenosis in randomized controlled trials but were significant for cohort studies. Hence this shows the heterogeneity of the available data in the literature and the result is dependent on what studies you include in the review. Another reason why the outcome data is variable is that the high-speed blood flow in dialysis access circuits washes a large amount of the paclitaxel away from the target lesion soon after application. A measurement in swine showed that only 20%-30% of paclitaxel was taken up into the coronary artery wall in vivo 15-25minutes after PCB application. Furthermore, recent attention has been drawn to a possible increase in late mortality signal and lower amputation free survival in patients receiving DCB treatment with paclitaxel for peripheral arterial disease, although this suggestion has not been demonstrated in the data of DCB within the fistula circuit either at 1 or 2 years. In light of these concerns, attention has turned away recently from paclitaxel-based technologies to sirolimus coated platforms. Sirolimus, like paclitaxel, is a potent antiproliferative agent, which has been found to prevent restenosis in the coronary bed and more recently in the peripheral vasculature but to date has not been studied in AVF circuits The aims of the study is to determine the safety and efficacy of the MedAlliance SELUTION SLR 018™ DEB in the treatment of failing AV fistula due to conduit stenosis in patients undergoing renal dialysis.

Official Title
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Intervention With Selution SLR™ Agent Balloon for Endovascular Latent Limus Therapy for Failing AV Fistulas (ISABELLA) Trial

Conditions
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Arteriovenous Fistula, Dialysis Access Malfunction

Intervention / Treatment
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* Device: Selution SLR™ 018 Drug Eluting Balloon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged ≥21 years and ≤90 years Native AVF was created more than 2 months prior to the index procedure and had undergone 10 or more haemodialysis sessions utilising two needles Target lesion location has to be located between the anastomoses to the auxiliary-subclavian vein junction, as defined by insertion of the cephalopods vein On initial fistulogram, target lesion stenosis has to be >50% on angiographic assessment and in keeping with the clinical indicator for intervention Stenosis had to be < 12cm in length (to allow for potential treatment with one DEB (length 15cm) only) Stenosis had to be initially treated successfully with a high-pressure plain balloon prior to DEB treatment as defined by:- (A) No clinically significant dissection (flow limiting) (B) No extravasated requiring treatment/Stenting (C) Residual stenosis ≤30% by angiographic measurement (D) Ability to completely efface the lesion waist using the pre-dilation CBA No more than one additional (non-target) lesion in the access circuit that had to be also successfully treated (≤30% residual stenosis) before drug elation. Separate lesion was defined by at least 3cm in distance from the target lesion Reference vessel diameters allowed are 4mm - 7mm Exclusion Criteria: Women who are pregnant, lactating or planning on becoming pregnant during study Subject has more than two lesions in the access circuit Subject had a secondary non-target lesion that could not be successfully treated Sepsis or active infection Asymptomatic target lesions A thrombosis access or an access with thrombosis treated ≤30 days prior to the index procedure Pseudoaneurysm in proposed target lesion area Surgical revision of the access site performed, planned or expected ≤3 months before or after the index procedure Patients who is taking immunosuppressive therapy or are routinely taking ≥15mg of prednisone per day Currently participating in another investigational drug, biologic, or device study involving Sirolimus or Paclitaxel Contraindication to aspirin or clopidogrel usage Mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, or language barrier such that the subject is unable to give informed consent. Uncooperative attitude or potential for non-compliance with the requirements of the protocol making study participation impractical Where final angioplasty treatment requires a stent or drug eluting balloon >8mm in diameter Metastatic cancer or terminal medical condition Blood coagulation disorders Limited life expectancy (<12 months) Allergy or other known contraindication to iodinated media contrast, heparin, or Sirolimus

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Selution SLR™ 018 Drug Eluting Balloon<br>Subjects will undergo fistuloplasty with the study device - Selution SLR™ 018 Drug Eluting Balloon | Device: Selution SLR™ 018 Drug Eluting Balloon<br>* Target lesion will be pre-dilated with high pressure non-compliant balloon, then treated with SELUTION SLR™ 018 DEB Balloon.<br>* Other names: Sirolimus DEB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target Lesion Primary Patency | Defined as patency with no re-intervention to the area treated by SELUTION SLR™ DEB and a duplex-defined stenosis within the index-treated segment of <50%. TLPP ends when any of the following occur:- 1) clinically driven re-intervention to the treated segment, 2) thrombotic occlusions that includes the treatment segment, 3) surgical intervention that excludes the treatment segment from the access circuit, 4) abandonment of the AVF due to an inability to treat the target lesion, 5) duplex finding of more than 50% stenosis. | 6 months post-index procedure | 
| Freedom from adverse events | Freedom from events including thrombosis, life-threatening events or those resulting in death, requiring hospitalisation, resulting in permanent disability, requiring intervention to prevent permanent impairment. | 30 days post-index procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from any serious adverse event(s) involving the AV access circuit or the patient |  | 3 and 6 months post-index procedure | 
| Target Lesion Primary Patency and Access circuit primary patency | Defined as patency with no re-intervention to the area treated by SELUTION SLR™ DEB and a duplex-defined stenosis within the index-treated segment of <50%. TLPP ends when any of the following occur:- 1) clinically driven re-intervention to the treated segment, 2) thrombotic occlusions that includes the treatment segment, 3) surgical intervention that excludes the treatment segment from the access circuit, 4) abandonment of the AVF due to an inability to treat the target lesion, 5) duplex finding of more than 50% stenosis. | 3 months post index procedure | 
| Device Success | Successful balloon inflation of the SELUTION catheter for more than 2 minutes and retrieval of the catheter | Intra-operative | 
| Anatomical Success | <30% residual stenosis diameter measured immediately after an angioplasty | Immediately post-op | 
| Clinical Success | Improvement from baseline in the clinical or hemodynamic parameter (e.g. blood flow, venous pressure) that was the initial indicator of fistula dysfunction and the resumption of normal hemodialysis for a minimum of at least 1 session following the procedure | 1 week post-index procedure | 
| Need for open revision surgery |  | 2 years post-index procedure | 
| Secondary patency | Interval after intervention until access circuit is abandoned, including reinterventions to reestablish access flow. | 3 months and 6 months post-index procedure | 
| Access circuit thrombosis |  | 2 years post-index procedure | 
| Number of interventions required to maintain access circuit patency |  | 3 and 6 months post-index procedure | 
| Mortality rate |  | 3 and 6 months post-index procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug-Coated Balloons, Sirolimus, Arteriovenous Fistula, Fistuloplasty