title: Human type I pancreatic elastase treatment of arteriovenous fistulas in patients with chronic kidney disease.
abstract: OBJECTIVE
  This study explored the safety and efficacy of recombinant type I pancreatic elastase (PRT-201) topically applied once to the external surface of an arteriovenous fistula.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled trial. Adults with kidney disease undergoing creation of a radiocephalic fistula (RCF) or brachiocephalic fistula were randomized to treatment with placebo (n = 51), PRT-201 at 10 μg (n = 51), or PRT-201 at 30 μg (n = 49). The primary efficacy measure was unassisted primary patency (PP) over 1 year. Secondary efficacy measures were secondary patency (SP), unassisted maturation by ultrasound interrogation, use for hemodialysis, and hemodynamically significant lumen stenosis.
  
  
  RESULTS
  Median PP was 224 days for placebo and >365 days for the PRT-201 groups. At 1 year, 45%, 54%, and 53% of placebo, 10-μg, and 30-μg patients retained PP. The risk of PP loss was nonsignificantly reduced for 10 μg (hazard ratio [HR], 0.69; P = .19) and 30 μg (HR, 0.67; P = .17) vs placebo. In the subset (44% of patients) with a RCF, the median PP was 125 days for placebo and >365 days for the PRT-201 groups. At 1 year, 31%, 50%, and 63% of placebo, 10-μg, and 30-μg RCFs retained PP. The risk of RCF PP loss was nonsignificantly reduced by 10 μg (HR, 0.59; P = .18) and significantly reduced by 30 μg (HR, 0.37; P = .02) vs placebo. At 1 year, 77%, 81%, and 83% of placebo, 10-μg, and 30-μg patients retained SP. The risk of SP loss was nonsignificantly reduced for 10 μg (HR, 0.79; P = .61) and 30 μg (HR, 0.76; P = .55) vs placebo. In the subset with RCFs, 65%, 82%, and 90% of placebo, 10-μg, and 30-μg patients retained SP at 1 year. The risk of RCF SP loss was nonsignificantly reduced for 10 μg (HR, 0.45; P = .19) and 30 μg (HR, 0.27; P = .08) vs placebo. At month 3, 67%, 87% (P = .03), and 92% (P < .01) of the placebo, 10-μg, and 30-μg group fistulas had unassisted maturation by ultrasound interrogation. At month 3 in the subset with an RCF, 47%, 74% (P = .17), and 93% (P < .01) of placebo, 10-μg, and 30-μg group fistulas had unassisted maturation by ultrasound interrogation. Adverse event reports were not meaningfully different between groups.
  
  
  CONCLUSIONS
  PRT-201 appeared safe. The primary efficacy end point was not met. However, both PRT-201 doses were associated with improved unassisted maturation. The 30-μg dose was associated with increased PP in the subset with RCF.
authors.affiliation: Vascular Surgery, Kaiser Permanente, San Diego, Calif.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hye
authors.affiliation: Department of Cardiovascular Surgery, The Methodist Hospital, Houston, Tex.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Peden
authors.affiliation: Renal Care Associates, Peoria, Ill.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: O'Connor
authors.affiliation: California Institute of Renal Research, San Diego, Calif.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Browne
authors.affiliation: Department of Medicine, University of Iowa Hospital and Clinics, Iowa City, Iowa.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Dixon
authors.affiliation: Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, Mass.
authors.forename: Andres S
authors.initials: AS
authors.lastname: Schanzer
authors.affiliation: Transplant Program, Rush University Medical Center, Chicago, Ill.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Jensik
authors.affiliation: Renal-Electrolyte and Hypertension Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dember
authors.affiliation: VasCore, the Vascular Ultrasound Core Laboratory, Massachusetts General Hospital, Boston, Mass.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jaff
authors.affiliation: Research and Development, Proteon Therapeutics Inc, Waltham, Mass. Electronic address: sburke@proteontx.com.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Burke
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D003251:Constriction, Pathologic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006083:Graft Occlusion, Vascular / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010196:Pancreatic Elastase; D011994:Recombinant Proteins / Q000008:administration & dosage; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome; D014463:Ultrasonography; D014481:United States; D034941:Upper Extremity / Q000098:blood supply*; D014654:Vascular Patency / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D011994:Recombinant Proteins; D010196:Pancreatic Elastase; C017130:cholesterol-binding protein