The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation
NCT ID: NCT02013037
Last Updated: 2021-05-03
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
36 participants
INTERVENTIONAL
2012-11-30
2020-04-30
Brief Summary
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Detailed Description
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A central component of antibody-mediated cell injury is complement activation. The inhibition of terminal complement activation may be the missing link to decreasing possibly both complement-mediated AMR and cellular rejection (CR) by inhibiting both the inflammatory effects of both circulating antibodies and cytokine induced cell death.
Eculizumab is a monoclonal antibody that specifically binds to complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. By this mechanism, eculizumab (Soliris®) inhibits terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria patients.
This study is a non-randomized, open-label, investigator-initiated safety and efficacy trial investigating the de-novo use of eculizumab alongside conventional therapy to prevent antibody mediated rejection. The duration of the study will include an open enrollment period and at least 12 months of follow-up (post-transplant). We will consent up to 45 eligible patients, highly "sensitized", with a panel reactive antibody score greater than 70%, who are not previously or currently enrolled in another ongoing trial. Of these 45 participants, up to 20 of these patients will be treated with eculizumab (Solaris), the study drug. The use of eculizumab will be un-blinded to all study and research practitioner participants.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Eculizumab
Administration of Eculizumab to heart transplant recipients at Cedars Sinai Medical Center with a panel reactive antibody (PRA) ≥ 70%, for the prevention of antibody-mediated rejection.
Eculizumab
At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses.
On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion.
On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days.
On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit.
On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit.
Interventions
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Eculizumab
At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses.
On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion.
On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days.
On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit.
On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Patient has a panel reactive antibody (PRA) ≥ 70% at any time prior to screening.
* Patient is considered compliant and intends to be available for a minimum follow-up study period of 1 year.
* Patient must be vaccinated against Neisseria meningitides at least 2 weeks prior to receiving treatment therapy or receive appropriate antibiotic prophylaxis for the duration of eculizumab treatment if timely vaccination could not be achieved prior to transplantation.
* Voluntary written informed consent must be obtained before performance of any study-related procedure not considered routine medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
* Female subject is either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for up to 2 months after the last dose of study medication.
Exclusion Criteria
* Cold ischemia time is \> 6 hours.
* Current clinical, radiographic, or laboratory evidence of active or latent tuberculosis (TB), as determined by local standard of care.
* History of active TB within the last 2 years, even if treated.
* History of active TB greater than 2 years ago, unless there is documentation of adequate treatment according to locally accepted clinical practice.
(Note: Patients at risk of TB reactivation preclude administration of conventional immunosuppression, as determined by the study investigator and based upon appropriate evaluation).
* Receipt of desensitization treatment with rituximab less than 2 weeks prior to therapy and cluster of differentiation antigen 20 (CD20) count \>2%.
* Receipt of a live vaccine within 4 weeks prior to study entry.
* Patients with current or recent severe systemic infections within the 2 weeks prior to transplantation.
* Prior history of splenectomy.
18 Years
75 Years
ALL
No
Sponsors
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Alexion Pharmaceuticals, Inc.
INDUSTRY
Cedars-Sinai Medical Center
OTHER
Responsible Party
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Jignesh Patel, MD, PhD
Medical Director of Heart Transplant Program, Cedars Sinai Heart Institute
Principal Investigators
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Jignesh Patel, M.D., Ph.D.
Role: PRINCIPAL_INVESTIGATOR
Cedars Sinai Medical Center and Heart Institute
Locations
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Cedars Sinai Medical Center, Heart Institute
Los Angeles, California, United States
Countries
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References
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Kfoury AG, Hammond ME, Snow GL, Drakos SG, Stehlik J, Fisher PW, Reid BB, Everitt MD, Bader FM, Renlund DG. Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection. J Heart Lung Transplant. 2009 Aug;28(8):781-4. doi: 10.1016/j.healun.2009.04.035.
Uber WE, Self SE, Van Bakel AB, Pereira NL. Acute antibody-mediated rejection following heart transplantation. Am J Transplant. 2007 Sep;7(9):2064-74. doi: 10.1111/j.1600-6143.2007.01900.x. Epub 2007 Jul 5.
Wu GW, Kobashigawa JA, Fishbein MC, Patel JK, Kittleson MM, Reed EF, Kiyosaki KK, Ardehali A. Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. J Heart Lung Transplant. 2009 May;28(5):417-22. doi: 10.1016/j.healun.2009.01.015. Epub 2009 Mar 14.
Michaels PJ, Espejo ML, Kobashigawa J, Alejos JC, Burch C, Takemoto S, Reed EF, Fishbein MC. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant. 2003 Jan;22(1):58-69. doi: 10.1016/s1053-2498(02)00472-2.
Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, Cosio FG, Gandhi MJ, Kremers W, Gloor JM. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011 Nov;11(11):2405-13. doi: 10.1111/j.1600-6143.2011.03757.x. Epub 2011 Sep 22.
Nwakanma LU, Williams JA, Weiss ES, Russell SD, Baumgartner WA, Conte JV. Influence of pretransplant panel-reactive antibody on outcomes in 8,160 heart transplant recipients in recent era. Ann Thorac Surg. 2007 Nov;84(5):1556-62; discussion 1562-3. doi: 10.1016/j.athoracsur.2007.05.095.
Kobashigawa J, Crespo-Leiro MG, Ensminger SM, Reichenspurner H, Angelini A, Berry G, Burke M, Czer L, Hiemann N, Kfoury AG, Mancini D, Mohacsi P, Patel J, Pereira N, Platt JL, Reed EF, Reinsmoen N, Rodriguez ER, Rose ML, Russell SD, Starling R, Suciu-Foca N, Tallaj J, Taylor DO, Van Bakel A, West L, Zeevi A, Zuckermann A; Consensus Conference Participants. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2011 Mar;30(3):252-69. doi: 10.1016/j.healun.2010.11.003.
Berry GJ, Angelini A, Burke MM, Bruneval P, Fishbein MC, Hammond E, Miller D, Neil D, Revelo MP, Rodriguez ER, Stewart S, Tan CD, Winters GL, Kobashigawa J, Mehra MR. The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005-2011). J Heart Lung Transplant. 2011 Jun;30(6):601-11. doi: 10.1016/j.healun.2011.02.015. No abstract available.
Locke JE, Magro CM, Singer AL, Segev DL, Haas M, Hillel AT, King KE, Kraus E, Lees LM, Melancon JK, Stewart ZA, Warren DS, Zachary AA, Montgomery RA. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009 Jan;9(1):231-5. doi: 10.1111/j.1600-6143.2008.02451.x. Epub 2008 Oct 31.
Wang H, Arp J, Liu W, Faas SJ, Jiang J, Gies DR, Ramcharran S, Garcia B, Zhong R, Rother RP. Inhibition of terminal complement components in presensitized transplant recipients prevents antibody-mediated rejection leading to long-term graft survival and accommodation. J Immunol. 2007 Oct 1;179(7):4451-63. doi: 10.4049/jimmunol.179.7.4451.
Thomas TC, Rollins SA, Rother RP, Giannoni MA, Hartman SL, Elliott EA, Nye SH, Matis LA, Squinto SP, Evans MJ. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol. 1996 Dec;33(17-18):1389-401. doi: 10.1016/s0161-5890(96)00078-8.
Rinder CS, Rinder HM, Smith BR, Fitch JC, Smith MJ, Tracey JB, Matis LA, Squinto SP, Rollins SA. Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest. 1995 Sep;96(3):1564-72. doi: 10.1172/JCI118195.
Coutance G, Kobashigawa JA, Kransdorf E, Loupy A, Desire E, Kittleson M, Patel JK. Intermediate-term outcomes of complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients. J Heart Lung Transplant. 2023 Oct;42(10):1464-1468. doi: 10.1016/j.healun.2023.05.005. Epub 2023 May 12.
Patel JK, Coutance G, Loupy A, Dilibero D, Hamilton M, Kittleson M, Kransdorf E, Azarbal B, Seguchi O, Zhang X, Chang D, Geft D, Czer L, Varnous S, Kobashigawa JA. Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients. Am J Transplant. 2021 Jul;21(7):2479-2488. doi: 10.1111/ajt.16420. Epub 2021 Feb 11.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan: Study Protocol including Statistical Analysis Plan
Other Identifiers
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Pro00028970
Identifier Type: OTHER
Identifier Source: secondary_id
CSR 205237
Identifier Type: -
Identifier Source: org_study_id
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