Multicenter phase I/II trial of the safety of allogeneic endothelial cell implants after the creation of arteriovenous access for hemodialysis use: The V-HEALTH study
Part of the work described in this manuscript was presented in poster form at the American Society of Nephrology 2008 Annual Meeting in Philadelphia, Penn and as an oral presentation at the Thirty-fifth Annual VEITHsymposium™ in 2008.
Received 3 May 2009; accepted 25 July 2009.
Objectives
Vascular access dysfunction is the major cause of morbidity in patients on hemodialysis to treat end stage renal disease. Preclinical studies have demonstrated that the perivascular placement of implants containing allogeneic aortic endothelial cells (Vascugel) reduces thrombosis, inflammation, stenosis and increases lumen diameter in porcine models of arteriovenous fistulae (AVF) and arteriovenous grafts (AVG). We conducted a phase I/II clinical study to investigate the safety of Vascugel placement around the surgical anastomotic sites of newly constructed dialysis accesses.
Methods
From July 2006 to August 2006, eight patients (4 AVG, 4 AVF) were treated with two Vascugel sponges at the venous anastomosis in the open–label phase I trial. From January 2007 to August 2007 57 patients (30 AVG and 27 AVF) were randomized in a 2:1 fashion to receive either Vascugel or control matrices (placebo) at surgery. The phase II AVG patients had sponges placed at both the venous and arterial anastomoses. All patients were followed for 24 weeks. The primary objective of the study was to demonstrate the safety (incidence of infection, intervention, and thrombosis) of Vascugel compared with placebo within 30 days post-surgery. Secondary endpoints included assessments of patency, lumen diameter, and immunologic sensitization to human leukocyte antigens (HLA) determined by measurement of panel reactive antibodies (PRA).
Results
There was no difference in early complication rates between the Vascugel and placebo groups at 4 weeks (10.9% vs 21.1%, respectively). There were no statistically significant differences in primary or assisted primary patency between the intent to treat groups at 24 weeks. Vascugel treated AVG had a primary patency rate of 38% and an assisted primary patency rate of 72% (vs 23% and 58%, respectively, for placebo). Vascugel treated AVF had a primary patency rate of 60% at 24 weeks and an assisted primary patency rate of 96% (vs 62% and 88%, respectively, for placebo). A greater than 30% increase in PRA was detected in 9 of the 46 (19.5%) Vascugel treated patients and one of the 19 (5.2%) placebo patients (P = .26) and was not associated with any evidence of local or systemic complications.
Conclusions
Targeted local therapy with perivascular, allogeneic endothelial cells is a safe and novel therapeutic approach that may be ideally suited to control the response to injury at surgical anastomoses. Larger randomized trials are needed to determine if Vascugel can prolong AVG or AVF patency.
aDepartment of Vascular and Endovascular Surgery, University of California, San Francisco, Calif
cTransplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, Mass
dCincinnati Dialysis Program, University of Cincinnati, Cincinnati, Ohio
eDepartment of Surgery, Duke University Medical Center, Durham, NC
Reprint requests: Michael S. Conte, University of California, San Francisco Division of Vascular and Endovascular Surgery, 400 Parnassus Avenue, Suite A581, San Francisco, CA 94143-0222
This study was supported by Pervasis Therapeutics.
Competition of interest: Dr Nugent is a cofounder and has company ownership in Pervasis Therapeutics. Drs Conte, Lawson, and Roy-Chaudhury are on Pervasis' advisory board and have been paid honorariums for corporate speaking and speakers' bureau participation. Mr Gaccione has been paid consultant fees by Pervasis Therapeutics.
Additional material for this article may be found online at www.jvascsurg.org.
The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest.
ABSTRACT