Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial

William H Marks, Nizam Mamode, Robert A Montgomery, Mark D Stegall, Lloyd E Ratner, Lynn D Cornell, Ajda T Rowshani, Robert B Colvin, Bradley Dain, Judith A Boice, Denis Glotz, C10-001 Study Group, John Kanellis, Graeme Russ, Nassim Kamar, Yvon Lebranchu, Christophe Legendre, Lionel Rostaing, Christian Hugo, Giacomo Colussi, Paolo Rigotti, Anna Reisaeter, Frederic Oppenheimer, Lars Mjörnstedt, Gunnar Tufveson, Robert Higgins, Philip Mason, Nicholas Torpey, Anil Chandraker, Matthew Cooper, Jose El-Amm, A Osama Gaber, Roslyn Mannon, Christopher Marsh, Anup Patel, Flavio Vincenti, Patricia West-Thielke, Joshua Wolf, Steve Woodle, William H Marks, Nizam Mamode, Robert A Montgomery, Mark D Stegall, Lloyd E Ratner, Lynn D Cornell, Ajda T Rowshani, Robert B Colvin, Bradley Dain, Judith A Boice, Denis Glotz, C10-001 Study Group, John Kanellis, Graeme Russ, Nassim Kamar, Yvon Lebranchu, Christophe Legendre, Lionel Rostaing, Christian Hugo, Giacomo Colussi, Paolo Rigotti, Anna Reisaeter, Frederic Oppenheimer, Lars Mjörnstedt, Gunnar Tufveson, Robert Higgins, Philip Mason, Nicholas Torpey, Anil Chandraker, Matthew Cooper, Jose El-Amm, A Osama Gaber, Roslyn Mannon, Christopher Marsh, Anup Patel, Flavio Vincenti, Patricia West-Thielke, Joshua Wolf, Steve Woodle

Abstract

We report results of a phase 2, randomized, multicenter, open-label, two-arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in sensitized recipients of living-donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy-proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow-up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living-donor kidney transplants (EudraCT 2010-019630-28).

Keywords: clinical research/practice; complement biology; donors and donation: living; immunosuppressant - fusion proteins and monoclonal antibodies; kidney transplantation/nephrology; rejection: antibody-mediated (ABMR); sensitization.

© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1
Figure 1
Study design. AMR, antibody‐mediated rejection; IVIg, intravenous immunoglobulin; MMF, mycophenolate mofetil; PP, plasmapheresis; SOC, standard of care; TAC, tacrolimus
Figure 2
Figure 2
Patient disposition. aFailed screening (n, %): did not meet inclusion/exclusion criteria (62, 22.5%), physician decision (n = 13, 4.7%), adverse event (3, 1.1%), withdrawal by patient (3, 1.1%), death (1, 0.4%), other (56, 20.4%). bScreened but not randomized (n, %): failed desensitization (18, 6.5%), adverse event (4, 1.5%), enrollment failure (3, 1.2%), failed inclusion/exclusion criteria (1, 0.4%), withdrawal by patient (1, 0.4%), other (6, 2.2%). cDid not receive treatment (n, %): donor changed mind (1, 0.4%), issues with donor kidney (1, 0.4%)
Figure 3
Figure 3
Graft survival through 36 months. Graft survival time was defined as the time from transplantation until the date of death or date of graft loss. A patient who did not die or have graft loss was censored at the time of last contact. *P = .209 at 36 months. SOC, standard of care

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