Multi-Drug Desensitization Protocol for Heart Transplant Candidates
Background: Patients may develop antibodies (human leukocyte antigen [HLA] alloantibodies) to other human tissues via pregnancy, transfusions or previous transplantation, which limits the ability to find an acceptable donor heart for transplantation. Such patients are at high risk for antibody mediated rejection, graft failure, and acute rejection (i.e. death). For successful transplantation, patients must receive organs from donors who lack the HLA antigens that correspond to their alloantibody specificities. No successful desensitization strategy currently exists.
Purpose: To determine if desensitization by deletion of immunologic memory with a multi-drug approach including anti-T and B cell therapies and anti-plasma cell therapy can effectively eliminate or significantly reduce alloantibody levels and permit highly sensitized patients to obtain a heart transplant. This therapy is anticipated to remove immunologic memory and will require re-immunization.
|Heart Transplantation||Drug: Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis (Multidrug Protocol)||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Multi-Drug Desensitization Protocol for Heart Transplant Candidates|
- Anti-HLA alloantibody reduction [ Time Frame: 218 days ]Proportion of highly sensitized heart transplant candidates, patients with a CPRA greater than 50%, who have desensitization therapy, who achieve a reduction in alloantibody such that their CPRA falls below 20% and thus become functionally transplantable.
- Proportion of Transplanted Patients [ Time Frame: Six years ]Proportion of patients, who are transplanted within one year of finishing desensitization therapy.
- Overall Safety [ Time Frame: Six years ]Overall safety of combined immunotherapy with rATG, rituximab, IVIG, and bortezomib
- Grade 3 Non-Hematologic Toxicities [ Time Frame: 583 days ]Incidence of grade 3 and above non-hematologic toxicities
- Peripheral Neuropathy [ Time Frame: 583 days ]Incidence of all grades of peripheral neuropathy
- CMV, PTLD, and PML [ Time Frame: Six years ]Incidence of cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD) and progressive multifocal leukoencephalopathy (PML)
- Infection [ Time Frame: 583 days ]Incidence of infection complication
- Cardiac Dysrhythmias and Heart Failure [ Time Frame: 583 days ]Incidence of exacerbation of cardiac dysrhythmias and heart failure
- Antibody Mediated Rejection [ Time Frame: Six years ]Incidence of antibody mediated rejection at 6 months and 1 year post transplant
- De Novo alloantibody or DSA Production Post Transplant [ Time Frame: Six years ]Proportion of patients who develop de novo or recurrent donor-specific alloantibody (DSA) production post-transplant
- DSA Negative Patients Post-Transplant [ Time Frame: Six years ]Proportion of patients who are DSA negative at 1 year following transplantation
- Allograft survival [ Time Frame: Six years ]Allograft survival at 67 and 12 months post transplant
- Acute Rejection [ Time Frame: Six years ]Proportion of allografts that have an acute rejection episode stratified according to International Society of Heart and Lung Transplantation (ISHLT) grade
- Non-Transplanted Patients [ Time Frame: Six years ]Proportion of patients who achieve a Calculated Panel Reactive Antibody test CPRA of < 20%, but are not transplanted within the study period.
- Serious Adverse Events [ Time Frame: Six years ]Incidence of death, allograft loss, hospitalization due to infection, and non-fatal serious adverse cardiac event (defined as acute myocardial infarction, congestive heart failure, need for percutaneous cardiac intervention, coronary artery bypass grafting, cardiac defibrillator placement, cerebral vascular accident, peripheral vascular disease) at 1 year
|Study Start Date:||July 2012|
|Study Completion Date:||May 2016|
|Primary Completion Date:||May 2016 (Final data collection date for primary outcome measure)|
Experimental: Elimination of Immunologic Memory
A Multi-drug regimen is used to delete immunologic memory in order to reduce or eliminate alloreactive anti-HLA antibodies in highly sensitized heart transplant candidates.
Drug: Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis (Multidrug Protocol)
Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01556347
|United States, Washington|
|Providence Sacred Heart Medical Center|
|Spokane, Washington, United States, 99204|
|Principal Investigator:||Tiimothy B Icenogle, MD||Providence Sacred Heart Medical Center|