Clinical trial NCT01327573: Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation
Official title: Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation: A Randomized, Open-Label, Pilot Intervention Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Kidney; Complications, Allograft
Keywords: chronic kidney allograft injury
complement protein
eculizumab
Kidney transplantation
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Alexion Pharmaceuticals, Inc.
First posted: 2011-04-01
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Baseline eGFR (Estimated Glomerular Filtration Rate)
timeFrame: Baseline
measure: Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6
timeFrame: Months 2,3,4,5,6
measure: Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR)
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
Study officials:
affiliation: Yale University
name: Sanjay Kulkarni, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43. doi: 10.1111/j.1600-6143.2004.00360.x.
citation: 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. doi: 10.1097/01.tp.0000251430.11723.b6.
citation: Al-Lamki RS, Bradley JR, Pober JS. Endothelial cells in allograft rejection. Transplantation. 2008 Nov 27;86(10):1340-8. doi: 10.1097/TP.0b013e3181891d8b.
citation: 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. doi: 10.1182/blood-2007-06-094136. Epub 2007 Nov 30.
citation: 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. doi: 10.1053/j.ajkd.2009.08.011. Epub 2009 Oct 25.