A Multi-center, Dose-escalation Study of Human type I Pancreatic Elastase (PRT-201) Administered after Arteriovenous Fistula Creation

Abstract

PurposeTo explore the safety and efficacy of PRT-201.MethodsRandomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.0033 to 9 mg) applied after arteriovenous fistula (AVF) creation. Participants were followed for one year. The primary outcome measure was safety. Efficacy measures were the proportion with intra-operative increases in AVF outflow vein diameter or blood flow ≥25% (primary), changes in outflow vein diameter and blood flow, AVF maturation and lumen stenosis by ultrasound criteria and AVF patency.ResultsThe adverse events in the PRT-201 group (n=45) were similar to those in the placebo group (n=21). There were no differences in the proportion with ≥25% increase in vein diameter or blood flow, successful maturation or lumen stenosis. There was no statistically significant difference in primary patency between the dose groups (placebo n=21, Low Dose n=16, Medium Dose n=17 and High Dose n=12). In a subgroup analysis that excluded three participants with early surgical failures, the hazard ratio (HR) for primary patency loss of Low Dose compared with placebo was 0.38 (95% CI 0.10-1.41, P=0.15). In a Cox model, Low Dose (HR 0.27, 95% CI 0.04-0.79, P=0.09), white race (HR 0.17, 95% CI 0.03-0.79, P=0.02), and age <65 years (HR 0.25, CI 0.05-1.15, P=0.08) were associated (P<0.10) with a decreased risk of primary patency loss.ConclusionsPRT-201 was not different from placebo for safety or efficacy measures. There was a suggestion for improved AVF primary patency with Low Dose PRT-201 that is now being studied in a larger clinical trial.

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

“…These early-phase studies of this drug to date have demonstrated safety and feasibility and have shown promising results with regard to patency outcomes (77)(78)(79). Given the promising results from early phase studies, an ongoing phase III randomized controlled clinical trial is evaluating perivascularly delivered elastase administered at the time of new radiocephalic AVF creation (NCT02110901).…”

Novel Therapies for Hemodialysis Vascular Access Dysfunction

“…Additionally, it is postulated that elastin fragments have chemotactic properties that could inhibit migration of myofibroblasts from the adventitial to the intima and thereby, inhibit neointimal hyperplasia. An early phase placebo-controlled, dose-escalation trial of human type I pancreatic elastase (NCT01305824) applied to the adventitial surface of the newly created AVFs found that the treatment was well tolerated (81). Larger trials of human type I pancreatic elastase for AVFs (NCT01305824) and AVGs (NCT01001351) have recently been completed, and the results are forthcoming.…”

Novel Paradigms for Dialysis Vascular Access

“…Two recent examples of perivascular-delivered therapies include (1) endothelial cell-loaded gel foam wraps and (2) recombinant elastase therapy. Both of these therapies have been tested in early-phase clinical trials and have shown safety and feasibility (50,51). A larger, multicenter, phase II study of endothelial cell-loaded gel foam wraps will be initiated in the United States in 2013.…”