Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation - Full Text View

Purpose

This study is designed to assess the effectiveness of eculizumab in recipients of kidney transplantation with donor-specific antibodies (DSA) and worsening kidney function and to assess if eculizumab improves endothelial cell injury in the kidney.

The investigators hypothesize that complement inhibition with eculizumab will reduce allograft injury, resulting from less complement-mediated injury of endothelial cells and less endothelial cell activation.

Condition	Intervention	Phase
Kidney; Complications, Allograft	Drug: eculizumab	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation: A Randomized, Open-Label, Pilot Intervention Trial

Resource links provided by NLM:

MedlinePlus related topics: Kidney Transplantation

Drug Information available for: Eculizumab

U.S. FDA Resources

Further study details as provided by Yale University:

Primary Outcome Measures:

Percent change in GFR [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
Percent change is calculated as the 6-month GFR minus the baseline GFR, divided by the baseline GFR Percent change will be compared between treatment groups with stratification by C4d status

Secondary Outcome Measures:

Number of circulating endothelial cells with evidence of injury and bound antibody and/or complement [ Time Frame: baseline, 3,6,9 months ] [ Designated as safety issue: No ]
mixed effects model to compare trajectory of in number of circulation endothelial cells with evidence of injury and bound antibody and/or complement between treatment groups
Number of endothelial expressed genes that correlate with humoral rejection [ Time Frame: baseline, 3,6,9 months ] [ Designated as safety issue: No ]
mixed effects models to compare trajectory of number of endothelial expressed genes that correlate with humoral rejection between treatment groups
Change in GFR [ Time Frame: Baseline, 3,6,9,12 months ] [ Designated as safety issue: No ]
Compare trajectories of GFR change and percent GFR change between treatment groups using repeated GFR measurements
Safety Analysis [ Time Frame: baseline, 3,6,9,12 month ] [ Designated as safety issue: Yes ]
Tabulation of treatment-emergent adverse events (categorical) by treatment group as well as evaluation of changes in laboratory parameters (CBC, chemistries) (continuous)

Estimated Enrollment:	20
Study Start Date:	March 2011
Estimated Study Completion Date:	September 2014
Estimated Primary Completion Date:	July 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Eculizumab eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus, MMF [mycophenolate mofetil ], prednisone)	Drug: eculizumab Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks Other Names: h5G1.1-mAb Soliris
No Intervention: no additional therapy patients in this arm will receive standard immunosuppression regimen (oral tacrolimus, MMF, prednisone only, no additional therapy

Detailed Description:

This study will address the clinical challenge that currently exists in the management of kidney transplant recipients who have developed de novo DSA, have deteriorating graft function, yet have no established treatment alternative.

This is a randomized, open-label, pilot intervention trial. Post transplant patients with deteriorating renal function (defined as 20% reduction in GFR) will be screened for the development of DSA and biopsied for the presence of C4d deposition. All patients with DSA and those meeting inclusion/exclusion criteria will undergo protocol renal biopsy and will be assessed for C4d deposition. Participants will be randomized to treatment with eculizumab plus standard of care (SOC) or SOC only. Randomization will be stratified by C4d status (C4d+/C4d-) with 10 subjects (7 eculizumab, 3 SOC only) in each stratum.

Eculizumab is an antibody that has been developed to inhibit the complement protein C5. Eculizumab will be delivered via IV according to the following schedule:

Eculizumab Induction 600mg IV every 7 days for 4 doses
Eculizumab 900mg IV 7 days later
Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Kidney transplant recipients greater than 6 months from the date of transplant
Must be on standard immunosuppression: tacrolimus, mycophenolate mofetil, prednisone and have stable tacrolimus trough levels over past 3 months
Deteriorating renal function, as defined by 20% reduction in GFR (MDRD calculation)
Presence of DSA, as defined as MFI > 1100
Renal biopsy demonstrating no diffuse, irreversible end-stage organ injury (i.e. stage IV Fibrosis)
Renal biopsy demonstrating C4d deposition (stratum 1) or no C4d deposition (stratum 2)

Exclusion Criteria:

History of CMV, BK, HSV or other viral infections
History of chronic, recurrent bacterial infections
Evidence of tubulitis on renal biopsy or other morphological features of acute cellular rejection or acute humoral rejection
Renal biopsy demonstrating diffuse, irreversible end-stage organ injury
Absolute GFR < 25 (MDRD calculation)
Inability to provide informed consent
History of poor vascular access
Refusal to use double barrier contraception during study participation
Patients actively enrolled in other clinical trials

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01327573

Locations

United States, Connecticut
Yale University	Recruiting
New Haven, Connecticut, United States, 06520
Contact: Sanjay Kulkarni, MD 203-785-2565
Contact: Ricarda Tomlin, BS ricarda.tomlin@yale.edu
Principal Investigator: Sanjay Kulkarni, MD

Sponsors and Collaborators

Sanjay Kulkarni

Alexion Pharmaceuticals

Investigators

Principal Investigator:

Sanjay Kulkarni, MD

Yale University

More Information

Publications:

Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43.

Worthington JE, McEwen A, McWilliam LJ, Picton ML, Martin S. Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome. Transplantation. 2007 Feb 27;83(4):398-403.

Al-Lamki RS, Bradley JR, Pober JS. Endothelial cells in allograft rejection. Transplantation. 2008 Nov 27;86(10):1340-8. Review.

Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30.

Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T. Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis. 2010 Apr;55(4):708-11. Epub 2009 Oct 25.

Responsible Party:	Sanjay Kulkarni, Associate Professor, Yale University
ClinicalTrials.gov Identifier:	NCT01327573 History of Changes
Other Study ID Numbers:	AI-EC-0017
Study First Received:	March 30, 2011
Last Updated:	January 23, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Yale University:

chronic kidney allograft injury
complement protein
eculizumab
Kidney transplantation

Additional relevant MeSH terms:

Complement System Proteins
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on June 18, 2013