Safety and Dose Finding Study of Xigris in Hemodialysis Patients (Xigris1003)

Safety and Dose Finding Study of Xigris (Drotrecogin Alfa Activated) as an Anti-coagulant in End Stage Renal Disease (ESRD) Patients Treated With Hemodialysis (HD)

The purpose of the study is to assess the safety of Xigris (Drotrecogin alfa) as an anticoagulant at different dose levels during dialysis treatment in patients with End Stage Renal Disease (ESRD).

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease
• Intervention / Treatment: Drug: Drotrecogin alfa activated (Xigris)

Detailed Description

In United States, there are over 300,000 patients with ESRD who require hemodialysis. Clinical hemodialysis takes place three times a week and is dependent on adequate anticoagulation throughout the three to four hour procedure. Infection is one of the most common causes of death for patients with ESRD treated with hemodialysis (25%).

Xigris (drotrecogin alfa activated) is a recombinant form of human activated protein C and is successfully used for treatment of adult patients with severe sepsis. In addition to its fibrinolytic properties, drotrecogin alpha has both an anti-inflammatory effect, and an anti-coagulant effect. However, there are few safety and no efficacy data on the effect of Xigris in ESRD patients as an anticoagulant.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • The George Washington University Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. >18
2. Usually used heparin with HD

Exclusion Criteria:

1. Plt <100
2. Pregnancy
3. H/o bleeding diathesis
4. H/o CVA
5. Pt on Ticlid/plavix/warfarin
6. SBP >200
7. BASELINE PTT>50
8. INR>1.6

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Xigris; Drotrecogin alfa activated (Xigris) used as anticoagulant in patients treated with hemodialysis.

Drug: Drotrecogin alfa activated (Xigris); We will test different dose regimens of Drotrecogin alfa activated (Xigris) to determine the optimal dose to achieve PTT between 65 and 100 secs. The initial patients will receive Xigris dosed at an infusion rate of 12 mcg/kg/h via pre-filter arterial drip chamber via a standard IV pump. The PTT will be assessed at baseline,15,30,60,120 and 180 mins. Xigris dose will be adjusted in the following patients if the afferent PTT rises above 100 secs (normal range 25-40 secs) or if PTT remains <65 secs. If PTT remains less than 65 secs, the dose will be increased to the second dose regiment of 18 mcg/kg/hr. The dose escalation will continue in increments of 6 mcg/kg/h to a maximum dose of 36 mcg/kg/h. Each patient will receive Xigris only once.; Other Names: Drotrecogin alfa (activated)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Partial Thromboplastin Time (PTT) at 15 Minutes	PTT level during a hemodialysis treatment will be used to assess the effectiveness of Xigris as an anticoagulant.	PTT level at 15 minutes after start up of Xigris during the hemodialysis treatment.
Mean Partial Thromboplastin Time (PTT) at 30 Minutes	PTT level during a hemodialysis treatment will be used to assess the effectiveness of Xigris as an anticoagulant.	PTT level at 30 minutes after start up of Xigris during the hemodialysis treatment.
Mean Partial Thromboplastin Time (PTT) at 60 Minutes	PTT level during a hemodialysis treatment will be used to assess the effectiveness of Xigris as an anticoagulant.	PTT level at 60 minutes after start up of Xigris during the hemodialysis treatment.
Mean Partial Thromboplastin Time (PTT) at 120 Minutes	PTT level during a hemodialysis treatment will be used to assess the effectiveness of Xigris as an anticoagulant.	PTT level at 120 minutes after start up of Xigris during the hemodialysis treatment.
Mean Partial Thromboplastin Time (PTT) at 180 Minutes	PTT level during a hemodialysis treatment will be used to assess the effectiveness of Xigris as an anticoagulant.	PTT level at 180 minutes after start up of Xigris during the hemodialysis treatment.

Collaborators and Investigators

• Sponsor: George Washington University
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Lakhmir S Chawla, MD, George Washington University

Publications and helpful links

General Publications

• Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. doi: 10.1056/NEJM200103083441001.
• Bleyer AJ, Russell GB, Satko SG. Sudden and cardiac death rates in hemodialysis patients. Kidney Int. 1999 Apr;55(4):1553-9. doi: 10.1046/j.1523-1755.1999.00391.x.
• Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription of patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med. 1981 Nov 12;305(20):1176-81. doi: 10.1056/NEJM198111123052003.
• Hakim RM, Held PJ, Stannard DC, Wolfe RA, Port FK, Daugirdas JT, Agodoa L. Effect of the dialysis membrane on mortality of chronic hemodialysis patients. Kidney Int. 1996 Aug;50(2):566-70. doi: 10.1038/ki.1996.350.
• Hakim RM, Breyer J, Ismail N, Schulman G. Effects of dose of dialysis on morbidity and mortality. Am J Kidney Dis. 1994 May;23(5):661-9. doi: 10.1016/s0272-6386(12)70276-7.
• Held PJ, Port FK, Webb RL, Wolfe RA, Bloembergen WE, Turenne MN, Holzman E, Ojo AO, Young EW, Mauger EA, et al. Excerpts from United States Renal Data System 1995 Annual Data Report. Am J Kidney Dis. 1995 Oct;26(4 Suppl 2):S1-186. No abstract available.
• Held PJ, Port FK, Wolfe RA, Stannard DC, Carroll CE, Daugirdas JT, Bloembergen WE, Greer JW, Hakim RM. The dose of hemodialysis and patient mortality. Kidney Int. 1996 Aug;50(2):550-6. doi: 10.1038/ki.1996.348.
• Kimmel PL, Peterson RA, Weihs KL, Simmens SJ, Alleyne S, Cruz I, Veis JH. Psychosocial factors, behavioral compliance and survival in urban hemodialysis patients. Kidney Int. 1998 Jul;54(1):245-54. doi: 10.1046/j.1523-1755.1998.00989.x.
• Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis. 1990 May;15(5):458-82. doi: 10.1016/s0272-6386(12)70364-5.
• Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med. 1993 Sep 30;329(14):1001-6. doi: 10.1056/NEJM199309303291404.
• Causes of death. USRDS. United States Renal Data System. Am J Kidney Dis. 1997 Aug;30(2 Suppl 1):S107-17. No abstract available.
• Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Weihs KL, Alleyne S, Cruz I, Yanovski JA, Veis JH. Immunologic function and survival in hemodialysis patients. Kidney Int. 1998 Jul;54(1):236-44. doi: 10.1046/j.1523-1755.1998.00981.x.
• Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis. 2000 Mar;35(3):469-76. doi: 10.1016/s0272-6386(00)70200-9.
• Kaysen GA. Biological basis of hypoalbuminemia in ESRD. J Am Soc Nephrol. 1998 Dec;9(12):2368-76. doi: 10.1681/ASN.V9122368.
• Patient mortality and survival. USRDS. United State Renal Data System. Am J Kidney Dis. 1997 Aug;30(2 Suppl 1):S86-106. No abstract available.
• Kaysen GA. Role of inflammation and its treatment in ESRD patients. Blood Purif. 2002;20(1):70-80. doi: 10.1159/000046988.
• Bologa RM, Levine DM, Parker TS, Cheigh JS, Serur D, Stenzel KH, Rubin AL. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis. 1998 Jul;32(1):107-14. doi: 10.1053/ajkd.1998.v32.pm9669431.
• Kaysen GA. C-reactive protein: a story half told. Semin Dial. 2000 May-Jun;13(3):143-6. doi: 10.1046/j.1525-139x.2000.00038.x. No abstract available.
• Owen WF, Lowrie EG. C-reactive protein as an outcome predictor for maintenance hemodialysis patients. Kidney Int. 1998 Aug;54(2):627-36. doi: 10.1046/j.1523-1755.1998.00032.x.
• Bernard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE Jr, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB, Helterbrand JD. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med. 2001 Nov;29(11):2051-9. doi: 10.1097/00003246-200111000-00003.
• Bernard GR, Macias WL, Joyce DE, Williams MD, Bailey J, Vincent JL. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. Crit Care. 2003 Apr;7(2):155-63. doi: 10.1186/cc2167. Epub 2003 Feb 28.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: July 14, 2010
• First Submitted That Met QC Criteria: October 21, 2010
• First Posted (Estimate): October 25, 2010

Study Record Updates

• Last Update Posted (Actual): February 3, 2022
• Last Update Submitted That Met QC Criteria: January 6, 2022
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Anticoagulation; Hemodialysis; Xigris; PTT
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Protein C; Drotrecogin alfa activated
• Other Study ID Numbers: F1K-MC-1003