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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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]

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

Intervention / Treatment
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* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eculizumab<br>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<br>* 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.<br>* Other names: Soliris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eculizumab, 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, monoclonal antibody, donor specific antibodies