The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation

NCT02013037 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CSR 205237Pro00028970
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

All individuals who receive a heart transplant are at risk for developing antibody-mediated rejection (AMR). An antibody is a protein produced by the body's immune system when it detects a foreign substance, called an antigen. The mechanism of an antibody is to attack an antigen. In antibody mediated rejection, antibodies will attack the transplanted heart, causing injury to the heart. The purpose of this investigation is to determine if a study drug, called eculizumab (Soliris), is safe to use in heart transplant recipients, and determine if it reduces risk of antibody-mediated rejection.

Conditions

Antibody-mediated Rejection; Hyperacute Rejection of Cardiac Transplant; Left Ventricular Dysfunction; Cardiac Allograft Vasculopathy; Heart Graft Dysfunction

Keywords

cardiac transplantation; immunosuppression; acute cellular rejection; antibody mediated rejection; sensitization; antibody production in cardiac patients; panel reactive antibodies; desensitization strategies in heart transplant patients; complement activation; complement c3d and c4d deposition; terminal complement inhibition; complement C5 binding; Eculizumab; monoclonal antibody; donor specific antibodies

Outcome Measures

Primary Outcomes (1)

• Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction

  The efficacy of Eculizumab will be assessed by a composite endpoint of: 1. the incidence of pathologic AMR with a Grade ≥ 2 2. the incidence of left ventricular dysfunction, as defined by a left ventricular ejection fraction (LVEF) ≤ 40% or a decrease of \>15% from baseline prior to the initiation of Eculizumab treatment.

  up to 26 weeks post heart transplant

Secondary Outcomes (7)

• Patient Survival at 12 Months Post Heart Transplantation

  1 year post heart transplant

• Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant

  6 months post heart transplant

• Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant

  1 year post heart transplant

• Number of Participants With Antibody Mediated Rejection (AMR)

  up to 1 year post heart transplant

• Number of Participants With of Acute Cellular Rejection (ACR)

  up to 1 year post heart transplant

Study Arms (1)

Eculizumab

EXPERIMENTAL

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.

Drug: Eculizumab

Interventions

Eculizumab DRUG

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.

Also known as: Soliris

Eculizumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient is ≥ 18 years of age.
• 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.

You may not qualify if:

• Donor or recipient age is \< 18 years or \> 75 years.
• 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.

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead
• Alexion Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Cedars Sinai Medical Center, Heart Institute

Los Angeles, California, 90048, United States

Location

Related Publications (14)

• 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.

  PMID: 19632573 BACKGROUND

• 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.

  PMID: 17614978 BACKGROUND

• 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.

  PMID: 19416767 BACKGROUND

• 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.

  PMID: 12531414 BACKGROUND

• 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.

  PMID: 21942930 BACKGROUND

• 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.

  PMID: 17954062 BACKGROUND

• 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.

  PMID: 21300295 BACKGROUND

• 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.

  PMID: 21555100 BACKGROUND

• 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.

  PMID: 18976298 BACKGROUND

• 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.

  PMID: 17878341 BACKGROUND

• 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.

  PMID: 9171898 BACKGROUND

• 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.

  PMID: 7657827 BACKGROUND

• 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.

  PMID: 37182818 DERIVED

• 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.

  PMID: 33251691 DERIVED

MeSH Terms

Conditions

Ventricular Dysfunction, Left; Complement Component 3 Deficiency, Autosomal Recessive

Interventions

eculizumab

Condition Hierarchy (Ancestors)

Ventricular Dysfunction; Heart Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Dr. Jignesh Patel
• Organization: Cedars Sinai Smidt Heart Institute

jignesh.patel@cshs.org

310-248-8300

Study Officials

• Jignesh Patel, M.D., Ph.D.

  Cedars Sinai Medical Center and Heart Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director of Heart Transplant Program, Cedars Sinai Heart Institute

Study Record Dates

• First Submitted: December 11, 2013
• First Posted: December 17, 2013
• Study Start: November 1, 2012
• Primary Completion: December 30, 2019
• Study Completion: April 30, 2020
• Last Updated: May 3, 2021
• Results First Posted: May 3, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data will be available following publication and ending 3 years following article publication.
• Access Criteria: Data will be available to investigators whose proposed used of the data has been approved by Cedars Sinai IRB.

Locations

US (1)