Arteriovenous Fistulae: Drug-eluting Balloon Angioplasty

Study Overview
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Brief Summary
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Dysfunctions such as tight stenosis or thrombosis in haemodialysis vascular accesses are the leading cause of hospitalisationand morbidity in chronic haemodialysis patients incurring significant related costs estimated at over one billion dollars in the USA. Dysfunctions of these vascular accesses are generally treated by conventional angioplasty as this is the least invasive procedure, the alternative being revision surgery. Angioplasty uses an inflatable balloon of various diameters. Different types of angioplasty balloons may be needed to break fibrous venous stenosis, in particular high-pressure balloons or cutting balloons. These angioplasty procedures which are often painful during dilation have a high technical success rate but a poor 1-year patency rate. These invasive repeated procedures impair the quality of life of these patients with end-stage renal disease who are on permanent dialysis or awaiting a kidney transplant and for whom vascular access patency is vital. Due to their traumatic effect on the vessel wall, these procedures induce cell proliferation processes that retrigger neointimal hyperplasia the very act of preserving the haemodialysis access is the key factor in development of a new stenosis and hence a vicious circle of stenosis-angioplasty. For the past few years, angioplasty balloons delivering anticancer drugs have been developed. These drugs, generally used in high doses for cancer chemotherapy, are released in small doses on the medical angioplasty devices. During inflation, the local release of the anticancer molecule through the different layers of the vessel wall confers local antiproliferative action without the systemic toxic effects associated with high-dose chemotherapy. These medical devices have demonstrated their efficacy in terms of increase in primary and secondary patency rates on procedures such as coronary artery angioplasty, femoro-popliteal or sub-popliteal artery angioplasty. These drug-eluting balloons (DEBs) are also CE marked with the recommendation of being indicated for AVF anticancerangioplasties, but no randomised multi-centre clinical trial has proven their medical effectiveness, and in particular their contribution in terms of patency rate improvement. However, studies on animal models show significant results regarding efficacy against neointimal hyperplasia and the first single-centre clinical trials on a small sample size appear promising. The key assessment criterion is primary patency of the dilated stenosis at one year defined by patients efficaciously dialysed at one year without re-intervention on the dilated lesion after initial angioplasty. The delay of occurrence of dilation will be considered. Patients that will be non-evaluable for the primary endpointwill be censored at the date of the latest news.

Detailed Description
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Dysfunctions such as tight stenosis or thrombosis in haemodialysis vascular accesses are the leading cause of hospitalisation (20%) and morbidity in chronic haemodialysis patients incurring significant related costs estimated at over one billion dollars in the USA. Dysfunctions of these vascular accesses are generally treated by conventional angioplasty as this is the least invasive procedure, the alternative being revision surgery. Angioplasty uses an inflatable balloon of various diameters. Different types of angioplasty balloons may be needed to break fibrous venous stenosis, in particular high-pressure balloons (20 atm) or cutting balloons. These angioplasty procedures which are often painful during dilation have a high technical success rate (90-97%) but a poor 1-year patency rate, varying between 26 and 64% depending on the team and a mean rate estimated at 40% for the studies including the larger number of patients, some of whom requiring several procedures. These invasive repeated procedures impair the quality of life of these patients with end-stage renal disease who are on permanent dialysis or awaiting a kidney transplant and for whom vascular access patency is vital. Due to their traumatic effect on the vessel wall, these procedures induce cell proliferation processes that retrigger neointimal hyperplasia the very act of preserving the haemodialysis access is the key factor in development of a new stenosis and hence a vicious circle of stenosis-angioplasty. For the past few years, angioplasty balloons delivering anticancer drugs (Paclitaxel, Sirolimus, Everolimus) have been developed. These drugs, generally used in high doses for cancer chemotherapy, are released in small doses on the medical angioplasty devices. During inflation, the local release of the anticancer (antimitotic) molecule through the different layers of the vessel wall (Paclitaxel is lipophilic and hydrophobic) confers local antiproliferative action without the systemic toxic effects associated with high-dose chemotherapy. These medical devices have demonstrated their efficacy in terms of increase in primary and secondary patency rates on procedures such as coronary artery angioplasty, femoro-popliteal or sub-popliteal artery angioplasty (treatment of angina or lower limb arteriopathy). These drug-eluting balloons (DEBs) are also CE marked with the recommendation of being indicated for AVF anticancerangioplasties, but no randomised multi-centre clinical trial has proven their medical effectiveness, and in particular their contribution in terms of patency rate improvement. However, studies on animal models show significant results regarding efficacy against neointimal hyperplasia and the first single-centre clinical trials on a small sample size appear promising. The key assessment criterion is primary patency of the dilated stenosis at one year defined by patients efficaciously dialysed at one year without re-intervention on the dilated lesion after initial angioplasty. The delay of occurrence of dilation will be considered (censored criteria). Patients that will be non-evaluable for the primary endpoint (death, lost to follow-up…) will be censored at the date of the latest news.

Official Title
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Fistules Artério-Veineuses: Angioplastie Par Ballon à Elution de Drogue (FAVABED) - Arteriovenous Fistulae: Drug-eluting Balloon Angioplasty

Conditions
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Stenosis of Arteriovenous Dialysis Fistula

Intervention / Treatment
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* Device: Paclitaxel (Taxol) eluting angioplasty balloon
* Device: high-pressure angioplasty balloon
* Device: low-pressure balloon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18, Stage 5 renal failure patients on permanent haemodialysis treatment (every 2 or 3 days), Native and efficient arteriovenous fistula > 3 months, 3mm ≤ reference vein diameter ≤ 8 mm and stenosis length ≤ 10 cm (range of DEB diameters and lengths), Absence of fistula thrombosis, Possibility of crossing the stenosis with a guide wire, Significant stenosis > 50% (in relation to the reference diameter) on the fistulogram, Clinical diagnosis of imminent fistula dysfunction pressure rise during dialysis and/or puncture difficulties and/or recirculation or poor extrarenal clearance and/or decrease in vascular access flow and/or increase in compression time after dialysis Social security affiliation, Receipt of free, informed, written consent. Exclusion Criteria: Multiple stenoses, Goretex® graft prostheses Systemic or local infection, Known allergy to contrast agent or Paclitaxel. Comorbidity not permitting long-term follow-up, Life expectancy < 1 year, Anticancer treatment (patients treated with chemotherapy for neoplasia), Pregnant or breastfeeding woman, Patients over 18 years of age who are under legal protection (conservatorship, trusteeship, guardianship), or deprived of freedom.

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: DEB arm<br>dilation by a high-pressure conventional angioplasty balloon (sized to fit the reference native vein diameter) until disappearance of the stenotic obstructive area and achievement of technical success (possibility of changing balloon size or dilation pressure) then dilation by a DEB. | Device: Paclitaxel (Taxol) eluting angioplasty balloon<br>* Dilatation by a high-pressure conventional angioplasty balloon untill disappearance of the stenosis obstructive area and achievement of technical success. Then dilatation by a DEB of the same size for 2 minutes.<br>* Other names: BARD, Lutonix® 035 and Lutonix®5F GeoAlign™;Device: high-pressure angioplasty balloon<br>* Dilatation by a high-pressure conventional angioplasty balloon untill disappearance of the stenosis obstructive area and achievement of technical success. Then dilatation either by a shame balloon or by a DEB balloon of the same size for 2 minutes.<br>* Other names: BARD, Conquest®;|
| Active Comparator: conventional angioplasty arm<br>dilation will be performed by a conventional high-pressure balloon until technical success is achieved (possibility of changing balloon size or dilation pressure), then by a sham balloon i.e a conventional low-pressure balloon (placebo) | Device: high-pressure angioplasty balloon<br>* Dilatation by a high-pressure conventional angioplasty balloon untill disappearance of the stenosis obstructive area and achievement of technical success. Then dilatation either by a shame balloon or by a DEB balloon of the same size for 2 minutes.<br>* Other names: BARD, Conquest®;Device: low-pressure balloon<br>* Dilatation by a high-pressure conventional angioplasty balloon untill disappearance of the stenosis obstructive area and achievement of technical success. Thenn dilatation by a shame balloon i.e conventional low pression balloon of the same size for 2 minutes.<br>* Other names: BARD, Ultraverse®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients whose haemodialysis is efficient at 1 year without needing further treatment of the stenotic site after initial angioplasty | assess the primary patency at 1 year after the dilatation of native AVF stenosis with active drug-eluting balloons (DEB) compared to conventional plain balloons, i.e to compare between the two groups the number of patients whose haemodialysis is efficient at 1 year without needing further treatment of the stenotic site after initial angioplasty. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| primary patency at 6 months | assess the advantages of Drug-Eluting Balloon compared to conventional plain balloon for primary patency at 6 months of the dilated stenosis | 6 months | 
| overall primary patency of the Arteriovenous Fistula at 1 year | assess the advantages of Drug-Eluting Balloon compared to conventional plain balloon for overall primary patency of the Arteriovenous Fistula at 1 year (patency including AVF dysfunction in relation to the initial dilated stenosis as well as stenoses distant from the initially treated site) | 1 year | 
| assisted primary patency of the dilated stenosis at 1 year | assess the advantages of Drug-Eluting Balloon compared to conventional plain balloon for assisted primary patency of the dilated stenosis at 1 year: Arteriovenous Fistula patency and continuation of efficient haemodialysis sessions with new angioplasties on the initially dilated stenotic site (excluding de-obstruction for complete thrombosis) | 1 year | 
| secondary patency of the AVF at 1 year | assess the advantages of Drug-Eluting Balloon compared to conventional plain balloon for secondary patency of the Arteriovenous Fistula at 1 year: Arteriovenous Fistula patency and continuation of efficient haemodialysis sessions also including complete thrombosis de-obstruction procedures | 1 year | 
| The minimal diameter of the treated stenosis and the AVF flows | assess the advantages of Drug-Eluting Balloon compared to conventional plain balloon for the minimal diameter of the treated stenosis (Late Luminal Loss) and the Arteriovenous Fistula flows (both criterion being evaluated by Doppler ultrasound and Transonic® after angioplasty, and at 6 months and 1 year follow-up). | 1 year | 
| Overall and cardiovascular survival | during analysis in sub-groups, the advantage of these Drug-Eluting Balloons for Overall and cardiovascular survival at 2 and 5 years for all patients and for subgroup of patients with symptomatic peripheral artery disease | 5 years |