Use of ABI-007 for the Prevention of Vascular Access Graft Failure in Patients Undergoing Hemodialysis

Study Overview
=================
Brief Summary
-----------------
This study is designed to confirm the safety of the proposed dose and schedule of ABI-007 for hemodialysis patients with vascular access device failure, and to obtain preliminary data on the effectiveness of such treatment.

Detailed Description
-----------------
This is an open-label, pilot, phase II study to assess the feasibility of administering ABI-007 intravenously [IV] over 3-5 minutes to patients with hemodialysis graft dysfunction (i.e., either a thrombosed polytetrafluoroethylene (PTFE) graft, or a patent but dysfunctional PTFE graft). Patients with graft dysfunction who are successfully treated with angioplasty will start treatment after angioplasty or during their first dialysis through the graft following intervention, and will receive 3 subsequent treatments of ABI-007 at 35 mg/m^2 on weeks 5, 13 and 21.

Official Title
-----------------
A Pilot Phase II Trial Of ABI-007 (A Cremophor El-Free, Protein Stabilized, Nanoparticle Paclitaxel) For The Prevention Of Vascular Access Graft Failure In Patients Undergoing Hemodialysis

Conditions
-----------------
Hemodialysis Graft Dysfunction

Intervention / Treatment
-----------------
* Drug: ABI-007


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Thrombosed graft within the past 7 days or a patent but dysfunctional polytetrafluoroethylene (PTFE) graft (identified by any means) with a stenosis of greater than 50% at the graft-vein anastomosis or within 8 centimeters of the graft-vein anastomosis which will be referred to as the index lesion. Following angioplasty patients must have residual stenosis of less than 20% post angioplasty for the index lesion and for all other stenoses; also index lesion must be located in the arm. PTFE graft requiring angioplasty must be at least 30 days old. Male or non-pregnant and non-lactating female, and ≥ 18 years of age. Patient or guardian has provided a signed written informed consent for the administration of ABI-007 (post-angioplasty or at the time of first dialysis through the new graft) using a form that is approved by the local IRB/ethics committee of the investigative site. Patient or his/her legally authorized representative or guardian has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent form prior to participation in any study-related activities. Exclusion Criteria: Use of a stent at the time of current angioplasty or at any previous time in the index lesion. No perforation at the time of current angioplasty. Thrombosed graft for more than 7 days. Patient has the following blood counts at baseline: Absolute neutrophil count (ANC) < 2.0*10^9/L; platelets < 100*10^9/L; Hemoglobin (Hgb) < 9 g/dL. Patient has the following blood chemistry levels at baseline: Aspartate transaminase (AST or SGOT), alanine transaminase (ALT or SGPT) > 2.5x upper limit of normal range (ULN); total bilirubin ≥ upper limit of normal (ULN); Unable to give informed consent, or for whom informed consent cannot be obtained from a legal guardian. Women who are pregnant and women of child bearing potential who do not use adequate contraception. 2 procedures of percutaneous or surgical intervention on the PTFE graft within the previous 90 days. Previous participation in another study with any investigational drug or device within the past 30 days or current enrollment in any other clinical protocol or investigational trial. Patient has a life expectancy of less than 6 months. Intended kidney transplant within 6 months of enrollment in the study Any significant medical condition which in the investigators opinion may interfere with the patients optimal participation in the study. Patient is, in the investigator's opinion, unlikely to be able to complete the study through the End of Study (EOS) visit. Patient has a history of allergy or hypersensitivity to the study drug. Documented hypercoagulable state requiring anti-coagulation (protein S, protein C, antiphospholipid; anticoagulation on an empiric basis for graft thromboses in not a contradiction). Patient is human immunodeficiency virus (HIV) positive. Patient is currently receiving other chemotherapy drug(s).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABI-007<br>ABI-007 35 mg/m^2 given intravenously (IV) into the arteriovenous (AV) graft within 96 hours after angioplasty, followed by repeat treatment during weeks 5, 13 and 21 | Drug: ABI-007<br> <br> * Other names: paclitaxel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Discontinued, Delayed or Interrupted Therapy | Percentage of participants who had discontinued therapy or had a delayed dose or an interrupted (omitted) dose due to toxicities/adverse events. | up to week 21 | 
| Percentage of Participants Without Graft Failure or Need for Intervention | Graft failure is defined as graft thrombosis, loss of vascular access function, or >50% stenosis of the index lesion at the time of a regularly scheduled angiographic assessment. | 24 weeks | 
| Stenosis (%) of the Index Lesion at Venous Anastomosis Using Angiography at Week 12 | Indexed lesion must be located in the arm and is a polytetrafluoroethylene (PTFE) thrombosed graft or a patent but dysfunctional PTFE graft with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the index lesion is measured by angiography. | 12 weeks | 
| Stenosis (%) of the Index Lesion at Venous Anastomosis Using Angiography at Week 24 | Indexed lesion must be located in the arm and is a polytetrafluoroethylene (PTFE) thrombosed graft or a patent but dysfunctional PTFE graft with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the index lesion is measured by angiography. | 24 weeks | 
| Stenosis (%) of the Index Lesion at Venous Anastomosis Using Angiography at Month 9 | Indexed lesion must be located in the arm and is a polytetrafluoroethylene (PTFE) thrombosed graft or a patent but dysfunctional PTFE graft with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the index lesion is measured by angiography. | 9 months | 
| Stenosis (%) of the Index Lesion at Venous Anastomosis Using Angiography at Month 12 | Indexed lesion must be located in the arm and is a polytetrafluoroethylene (PTFE) thrombosed graft or a patent but dysfunctional PTFE graft with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the index lesion is measured by angiography. | 12 months | 
| Stenosis (%) of a Non-index Lesion Using Angiography at Week 12 | Non-indexed lesion with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the non-index lesion is measured by angiography. Three non-index lesions are reported: central vein, intragraft and arterial anastomosis. | 12 weeks | 
| Stenosis (%) of a Non-index Lesion Using Angiography at Week 24 | Non-indexed lesion with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the non-index lesion is measured by angiography. Three non-index lesions are reported: central vein, intragraft and arterial anastomosis. | 24 weeks | 
| Stenosis (%) of a Non-index Lesion Using Angiography at Month 9 | Non-indexed lesion with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the non-index lesion is measured by angiography. Three non-index lesions are reported: central vein, intragraft and arterial anastomosis. | 9 months | 
| Stenosis (%) of a Non-index Lesion Using Angiography at Month 12 | Non-indexed lesion with a residual stenosis of less than 30% after the pre-dose angioplasty. The percent of stenosis (narrowing) of the non-index lesion is measured by angiography. Three non-index lesions are reported: central vein, intragraft and arterial anastomosis. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Arthrosclerotic Cardiovascular Complications | Counts of participants who had treatment-emergent arthrosclerotic cardiovascular complications, specifically myocardial infarction, arterial thromboses, or cerebrovascular events. | up to week 25 | 
| Kaplan Meier Estimates for Time to Graft Failure or Intervention | The time to graft failure or intervention was defined as the time from first dose of study drug to the first time graft failure or intervention. Participants who did not have graft failure or intervention at the end of the study were censored at the last known time that the participant had angiography. | up to 12 months | 
| Percentage of Participants With Patency of Index and Non-Index Lesions at 24 Weeks | The patency (unblocking) for index lesions is defined as <50% of stenosis and no PFTE graft thrombosis at 24 weeks. The patency for non-index lesions is defined as <50% of stenosis and no new non-index lesions at 24 weeks. | 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vascular Access Graft Failure, Venous Neointimal Hyperplasia(VNH), Hemodialysis