Delivery of Inhibitors of Lysyl Oxidase (LysoLox) on Serial Angioplasty and Time to Restenosis

Balloon Angioplasty of Dialysis AV Fistulae: Effect of Local Delivery of Inhibitors of Lysyl Oxidase (LysoLox) on Serial Angioplasty and Time to Restenosis

The narrowing of Dialysis Fistulae or Grafts is a near universal problem in patients with end-stage renal disease (ESRD) and requires patients to undergo repeated angioplasty or mechanical opening of the fistula.

Study Overview

• Status: Unknown
• Conditions: Arteriovenous Fistula Occlusion
• Intervention / Treatment: Drug: Placebo; Drug: Ascorbic Acid; Drug: Cuprimine Oral Product

Detailed Description

The failure of dialysis accesses remains a leading cause of morbidity and medical costs among ESRD subjects. The underlying etiology for dialysis access failure is uniformly due to progressive narrowing of the vessel lumen leading to stasis and thrombosis of the access. The luminal narrowing of arteriovenous fistulae (AVFs) is due to progressive hyperplasia of vessel intima and subsequent infiltration of smooth muscle cells into the vessel media. Areas of stenosis within AVFs are characterized by dense neointimal hyperplasia, infiltration of vascular smooth muscle cells and expansion of extracellular matrix material. Additionally, varying types of vascular injury increase the rate of collagen and elastin deposition within the medial and serosal areas of the vessel.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Chattanooga, Tennessee, United States, 37408
      • Recruiting
      • Southeast Renal Research Institute
      • Principal Investigator: James A Tumlin, MD
      • Contact: James A Tumlin, MD; Phone Number: 423-826-8003; Email: jamestumlinmd@nephassociates.com
      • Contact: Jeremy Whitson; Phone Number: 423-826-8003; Email: jeremywhitson@nephassociates.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 and < 90 years old
• Receiving stable out-subject hemodialysis for a minimum of 3 months
• Have a lower arm or upper arm AVF that has been cleared for use by the vascular surgeon or interventional nephrologist
• Have agreed to participate voluntarily and signed and dated an IRB approved, subject informed consent form

• Dysfunctional Dialysis Fistula: Any subject with

  • Two or more venous pressure readings exceeding 250 mmHg for a minimum of 5 minutes at a blood flow of 500mls/min within a single dialysis run AND a documented reduction in KT/V by > 0.2; OR
  • Patients with venous pressures > 250 mm Hg on two or more days within a 30 day period OR
  • Patients who on physical exam are found to have palpable obstructions, post-stenotic dilation of the access or evidence of prolonged post-dialysis bleeding.
• Any patient with one of the above conditions will be to have a dysfunctional AVF. This definition will be applied to the screening of study subjects as well as the determination of recurrent fistula dysfunction at 12 months.

Exclusion Criteria:

• Scheduled for surgical revision of the fistula;

• Have been in another investigational (non-approved) drug or device study within the previous 30 days;

  **have a known allergy to any component of the investigational product (drug or device)

• Subjects with a "Hero Graft" will be excluded from the study
• Subjects having received a stent for correction of a prior stenosis will be excluded from the trial
• Subjects with more than > 3 hemodynamically significant stenosis at one time (with the exception of a central venous stenosis)
• Subjects who are pregnant will be excluded from the trial (pregnancy test will be performed on subjects of child bearing potential). A urine pregnancy test will be utilized.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Low frequency angioplasty; Subjects who have had 0-1 angioplasty during the 12 months prior to randomization. Subjects will have endoluminal biopsy prior to angioplasty but will not have insertion of the ACT drug delivery catheter	Drug: Placebo; Subject will undergo endoluminal biopsy prior to angioplasty but will NOT undergo insertion of the ACT drug delivery catheter
Active Comparator: Moderate frequency angioplasty; Subjects who have had 2-3 angioplasties during the 12 months prior to randomization. Subjects will have endoluminal biopsy prior to angioplasty followed by insertion of the ACT drug delivery catheter where ascorbic acid (10.0 µM) will be injected following conventional balloon angioplasty	Drug: Ascorbic Acid; Subject will undergo endoluminal biopsy prior to angioplasty followed by insertion of the ACT drug delivery catheter where ascorbic acid (10.0 µM) will be injected following conventional balloon angioplasty
Active Comparator: High frequency angioplasty; High frequency angioplasty defined by 4 or more angioplasties 12 months prior to randomization. Subjects will receive ascorbic acid (10.0 µM) in combination with D-penicillamine (25 µM) will be injected following conventional balloon angioplasty	Drug: Cuprimine Oral Product; Subject will undergo endoluminal biopsy prior to angioplasty followed by insertion of the ACT drug delivery catheter where ascorbic acid (10.0 µM) in combination with D-penicillamine (25 µM) will be injected following conventional balloon angioplasty; Other Names: D-Penicillamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients treated with ascorbic acid in combination with D-penicillamine will have longer periods between serial angioplasties over 12-month period. Additionally, subjects receiving combination therapy may have greater post-angioplasty luminal diameters.	Subjects are followed for 12 months and monitored for signs of fistula dysfunction. When the patient's fistula becomes dysfunctional they will be referred for a fistulogram. The time between serial fistulograms will be recorded as a secondary endpoint. Patients who are referred for a repeat fistulogram and having a luminal narrowing of greater than 70% will undergo a second intimal biopsy.	12 months

Collaborators and Investigators

• Sponsor: Southeast Renal Research Institute
• Collaborators: Dialysis Clinic, Inc.
• Investigators: Principal Investigator: James A Tumlin, MD, Southeast Renal Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Anticipated): January 31, 2018
• Study Completion (Anticipated): March 1, 2018

Study Registration Dates

• First Submitted: February 15, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (Actual): April 11, 2017

Study Record Updates

• Last Update Posted (Actual): September 11, 2017
• Last Update Submitted That Met QC Criteria: September 6, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Pathological Conditions, Anatomical; Cardiovascular Abnormalities; Vascular Malformations; Arteriovenous Malformations; Vascular Fistula; Fistula; Arteriovenous Fistula; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Protective Agents; Micronutrients; Vitamins; Antioxidants; Antidotes; Chelating Agents; Sequestering Agents; Ascorbic Acid; Penicillamine
• Other Study ID Numbers: Lysyl Oxidase (LysoLox)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No