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

Left Ventricular Dysfunction Clinical Trial

— DUET  

Official title:

The De-novo Use of Eculizumab Alongside Conventional Therapy in Presensitized Patients Receiving Cardiac Transplantation: An Open-Label, Investigator-Initiated Pilot Trial: [The DUET Cardiac Trial]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02013037
• Other study ID #: CSR 205237
• Secondary ID: Pro00028970
• Status: Completed
• Phase: Phase 3
• Start date: November 2012
• Est. completion date: April 30, 2020

Study information

• Verified date: April 2021
• Source: Cedars-Sinai Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

The growing proportion of sensitized cardiac recipients presents an additional challenge to the transplant practitioner attempting to minimize the occurrence of antibody mediated rejection (AMR). Patients pre-exposed or "sensitized" to antigen exposing events (i.e.: blood transfusions, multiple pregnancies, prior organ transplantations, ventricular support devices) are more likely to both possess preformed and develop de-novo antibodies. Sensitized patients with panel reactive antibodies > 25% are at risk for increased risk of rejection, development of cardiac allograft vasculopathy and increased mortality after heart transplantation. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: April 30, 2020
• Est. primary completion date: December 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
United States	Cedars Sinai Medical Center, Heart Institute	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center	Alexion Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum in: Am J Transplant. 2013 Jan;13(1):241. — View Citation

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. — View Citation

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. Epub 2007 Jul 5. Review. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction	The efficacy of Eculizumab will be assessed by a composite endpoint of: the incidence of pathologic AMR with a Grade = 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	Patient Survival at 12 Months Post Heart Transplantation	The study will assess overall survival at 12 months following heart transplantation.	1 year post heart transplant
Secondary	Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant	The incidence of patient hemodynamic compromise will be assessed at 6 months post transplant, as defined by any one of the following: a 20% decrease in LVEF from baseline; a LVEF < 40%; a 25% decrease in cardiac index from baseline; a cardiac index < 2.0; the need for inotropic support	6 months post heart transplant
Secondary	Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant	The incidence of patient hemodynamic compromise will be assessed at one year post transplant, as defined by any one of the following: a 20% decrease in LVEF from baseline; a LVEF < 40%; a 25% decrease in cardiac index from baseline; a cardiac index < 2.0; the need for inotropic support	1 year post heart transplant
Secondary	Number of Participants With Antibody Mediated Rejection (AMR)	The study assessed the number of patients who develop AMR as well as the total number of episodes of AMR.	up to 1 year post heart transplant
Secondary	Number of Participants With of Acute Cellular Rejection (ACR)	The study assessed the number of participants with of Acute Cellular Rejection (ACR)	up to 1 year post heart transplant
Secondary	Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS)	Development of cardiac allograft vasculopathy at 1 year determined by intravascular ultrasound defined as change in site-matched maximal intimal thickness = 0.5mm from baseline to 1 year.	up to 1 year post heart transplant
Secondary	Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation	Number of Participants who develop de novo donor specific antibody (DSA) in the first year following transplantation was determined.	Up to 1 year post transplant