A multi-center, dose-escalation study of human type I pancreatic elastase (PRT-201) administered after arteriovenous fistula creation

Eric K Peden, David B Leeser, Bradley S Dixon, Mahmoud T El-Khatib, Prabir Roy-Chaudhury, Jeffrey H Lawson, Matthew T Menard, Laura M Dember, Marc H Glickman, Pamela N Gustafson, Andrew T Blair, Marianne Magill, F Nicholas Franano, Steven K Burke, Eric K Peden, David B Leeser, Bradley S Dixon, Mahmoud T El-Khatib, Prabir Roy-Chaudhury, Jeffrey H Lawson, Matthew T Menard, Laura M Dember, Marc H Glickman, Pamela N Gustafson, Andrew T Blair, Marianne Magill, F Nicholas Franano, Steven K Burke

Abstract

Purpose: To explore the safety and efficacy of PRT-201.

Methods: Randomized, 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.

Results: The 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.

Conclusions: PRT-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.

Trial registration: ClinicalTrials.gov NCT00679991.

Conflict of interest statement

Conflict of interest: Gustafson and Burke are employed by Proteon. Franano has ownership in Proteon and serves on the Board of Directors.

Figures

Fig. 1
Fig. 1
Participant flow throughout the study.
Fig. 2
Fig. 2
Kaplan-Meier plots of AVF unassisted primary patency for the All Treated population (A) and the All Treated Minus Surgical Failures population (B) that excludes three participants with early surgical failures.

References

    1. Allon M., Robbin M.L. Increasing arteriovenous fistulas in hemodialysis patients: problems and solutions. Kidney Int. 2002; 62(4): 1109–1124. doi: 10.1111/j.1523-1755.2002. kid551.x. Medline
    1. Vascular Access 2006 Work Group. Clinical practice guidelines for vascular access. Am J Kidney Dis. 2006; 48: S177–S247.
    1. Dember L.M., Kaufman J.S., Beck G.J. et al.; DAC Study Group. Design of the dialysis access consortium (DAC) clopidogrel prevention of early AV fistula thrombosis trial. Clin Trials. 2005; 2(5): 413–422. doi: 10.1191/1740774505cn118oa. Medline
    1. Asif A., Roy-Chaudhury P., Beathard G.A. Early arteriovenous fistula failure: a logical proposal for when and how to intervene. Clin J Am Soc Nephrol. 2006; 1(2): 332–339. doi: 10.2215/CJN.00850805. Medline
    1. Falk A. Maintenance and salvage of arteriovenous fistulas. J Vasc Interv Radiol. 2006; 17(5): 807–813. doi: 10.1097/01. RVI.0000217928.43396.35. Medline
    1. Robbin M.L., Chamberlain N.E., Lockhart M.E. et al. Hemodialysis arteriovenous fistula maturity: US evaluation. Radiology. 2002; 225(1): 59–64. doi: 10.1148/radiol.2251011367. Medline
    1. Dember LM, Beck GJ, Allon M, et al.; Dialysis Access Consortium Study Group. Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA. 2008; 299(18): 2164–2171. doi: 10.1001/jama.299.18.2164. Medline
    1. Roy-Chaudhury P., Sukhatme V.P., Cheung A.K. Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint. J Am Soc Nephrol. 2006; 17(4): 1112–1127. doi: 10.1681/ASN.2005050615. Medline
    1. Pisoni R.L., Young E.W., Dykstra D.M. et al. Vascular access use in Europe and the United States: results from the DOPPS. Kidney Int. 2002; 61(1): 305–316. doi: 10.1046/j.1523-1755.2002.00117.x. Medline
    1. Schinstock C.A., Albright R.C., Williams A.W. et al. Outcomes of arteriovenous fistula creation after the Fistula First Initiative. Clin J Am Soc Nephrol. 2011; 6(8): 1996–2002. doi: 10.2215/CJN.11251210. Medline
    1. Jackson R.S., Sidawy A.N., Amdur R.L., Khetarpal A., Macsata R.A. Angiotensin receptor blockers and antiplatelet agents are associated with improved primary patency after arteriovenous hemodialysis access placement. J Vasc Surg. 2011; 54(6): 1706–1712. doi: 10.1016/j.jvs.2011.06.028. Medline
    1. Ruddy J.M., Brothers T.E., Robison J.G., Elliott B.M. Increasing the proportion of autologous arteriovenous fistulas does not diminish fistula patency. Vasc Endovascular Surg. 2011; 45(1): 51–54. doi: 10.1177/1538574410388310. Medline
    1. Tessitore N., Mansueto G., Lipari G. et al. Endovascular versus surgical preemptive repair of forearm arteriovenous fistula juxta-anastomotic stenosis: analysis of data collected prospectively from 1999 to 2004. Clin J Am Soc Nephrol. 2006; 1(3): 448–454. doi: 10.2215/CJN.01351005. Medline
    1. Talas U., Dunlop J., Khalaf S., Leigh I.M., Kelsell D.P. Human elastase 1: evidence for expression in the skin and the identification of a frequent frameshift polymorphism. J Invest Dermatol. 2000; 114(1): 165–170. doi: 10.1046/j.1523-1747.2000.00825.x. Medline
    1. Tani T., Kawashima I., Furukawa H., Ohmine T., Takiguchi Y. Characterization of a silent gene for human pancreatic elastase I: structure of the 5′-flanking region. J Biochem. 1987; 101(3): 591–599. doi: 10.1093/jb/101.3.591. Medline
    1. Bieth J., Spiess B., Wermuth C.G. The synthesis and analytical use of a highly sensitive and convenient substrate of elastase. Biochem Med. 1974; 11(4): 350–357. doi: 10.1016/0006-2944(74)90134-3. Medline
    1. Dobrin P.B., Canfield T.R. Elastase, collagenase, and the biaxial elastic properties of dog carotid artery. Am J Physiol. 1984; 247(1 Pt 2): H124–H131 Medline.
    1. Qamar A.A., Burke S.K., Lafleur J.D. et al. The ability of serum from alpha 1-antitrypsin-deficient patients to inhibit PRT-201, a recombinant human type I pancreatic elastase. Biotechnol Appl Biochem. 2012; 59(1): 22–28. doi: 10.1002/bab.65. Medline
    1. Burke S.K., Franano F.N., Mendenhall V. et al. Recombinant human elastase (PRT-201) dilates outflow veins in a rabbit model of arteriovenous fistula. J Am Soc Nephrol. 2007; 18: 34A.
    1. Burke S.K., Franano F.N., LaRochelle A., Mendenhall H.V. Local application of recombinant human type I pancreatic elastase (PRT-201) to an arteriovenous fistula (AVF) increases AVF blood flow in a rabbit model. J Am Soc Nephrol. 2008; 19: 252A–253A.
    1. Franano F.N., Hance K., Bland K.S., Burke S.K. PRT-201 dilates outflow veins and improves maturation rates in a rabbit model of AVF. Nephrol Dial Transplant. 2007; 22: vi157.
    1. Hance K.A., Franano F.N., Henry C. et al. Prot-101 dilates AV fistula (AVF) outflow veins and reduces intimal hyperplasia in a rabbit model. J Am Soc Nephrol. 2005; 16: 11A.
    1. Beldi G., Bosshard A., Hess O.M., Althaus U., Walpoth B.H. Transit time flow measurement: experimental validation and comparison of three different systems. Ann Thorac Surg. 2000; 70(1): 212–217. doi: 10.1016/S0003-4975(00)01246-7. Medline
    1. Grogan J., Castilla M., Lozanski L., Griffin A., Loth F., Bassiouny H. Frequency of critical stenosis in primary arteriovenous fistulae before hemodialysis access: should duplex ultrasound surveillance be the standard of care? J Vasc Surg. 2005; 41(6): 1000–1006. doi: 10.1016/j.jvs.2005.02.019. Medline
    1. Corpataux J.M., Haesler E., Silacci P., Ris H.B., Hayoz D. Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access. Nephrol Dial Transplant. 2002; 17(6): 1057–1062. doi: 10.1093/ndt/17.6.1057. Medline
    1. Lee T., Ullah A., Allon M. et al. Decreased cumulative access survival in arteriovenous fistulas requiring interventions to promote maturation. Clin J Am Soc Nephrol. 2011; 6(3): 575–581. doi: 10.2215/CJN.06630810. Medline
    1. Burke S.K., Macdonald K., Bunton D., Starcher B., Ding B.C., Franano F.N. Time- and concentration-dependent effects of recombinant human elastase (PRT-201) on the elastin content of human upper extremity veins treated ex vivo. J Am Soc Nephrol. 2009; 20: 473A.
    1. Amabile P.G., Wong H., Uy M. et al. In vivo vascular engineering of vein grafts: directed migration of smooth muscle cells by perivascular release of elastase limits neointimal proliferation. J Vasc Interv Radiol. 2002; 13(7): 709–715. doi: 10.1016/S10510443-(07)61848-X. Medline
    1. Wong A.H., Waugh J.M., Amabile P.G., Yuksel E., Dake M.D. In vivo vascular engineering: directed migration of smooth muscle cells to limit neointima. Tissue Eng. 2002; 8(2): 189–199. doi: 10.1089/107632702753724969. Medline

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel