Multi-Drug Desensitization Protocol for Heart Transplant Candidates
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Percentage of Patients Who Suffer Mortality, a Serious Adverse Event, or Other Adverse Event During the Study Period
研究概览
简要总结
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.
详细描述
Transplant candidates with HLA alloantibodies are at high risk for antibody mediated rejection (AMR), graft failure, and acute rejection (1,2). In heart transplantation, these complications lead to death. The 50% calculated panel reactive antibody, CPRA, threshold is chosen from a consensus statement from the International Society of Heart and Lung Transplantation (3). This value is admittedly arbitrary but does represent a consensus of accepted opinion amongst experienced and reputable heart transplant centers.
The alloantibodies that prevent these patients from being transplanted are a result of the adaptive immune system and immunologic memory. Immunologic memory is defined as the ability of the immune system to provide a faster, stronger and more specific response to a second exposure of an antigen, when the antigen was completely eliminated from the organism after the prior exposure.
There are three major cell lines involved in immunologic memory: memory T cells, memory B cells and plasma cells, all of which can survive once antigen has been eliminated (4). B cells can mount responses to both small soluble antigens and large antigens (5). Once a B cell becomes activated, it can become a short lived plasma cell and produce immunoglobulin M, (IgM), antibodies or it can enter a germinal center where it can undergo somatic hypermutation with affinity maturation and isotype switching. The B cell can then differentiate into a long lived plasma cell and compete for a bone marrow niche or can become a memory B cell (4-8).
Memory T cells can last a lifetime and can recirculate between the secondary lymphoid organs (SLO) as central memory T cells (TCM) or in the peripheral tissues as effector memory T cells (TEM) (4,9). Upon encountering their cognate antigen, they can rapidly proliferate and differentiate to effector T cells.
Memory B cells slowly proliferate and recirculate in the SLOs, last there for decades and memory B cells to vaccinia (smallpox) have been noted to survive for more than 50 years (9). They are commonly identified by the presence of CD27 and upon a second antigenic challenge; the memory B cells can rapidly proliferate and then differentiate into new plasma cells (10). This phenomenon provides a redundant system or "array" to replenish plasma cells that produce antibody for a given antigen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 67 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntary signed informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
- •2.Female subject is either post-menopausal or surgically sterilized, or willing to use two acceptable methods of birth control for the duration of the study and for up to 2 months after the last dose of study medication.
- •3.Male subject agrees to use an acceptable method for contraception for the duration of the study.
- •4.Patient is greater than or equal to 18 years of age but less than 70 years old (inclusive).
- •5.Patients with a Calculated Panel Reactive Antibody (CPRA) of ≥ 50% by Luminex Single Antigen Flow Bead (SAFB) testing (LABScreen®, Canoga Park, CA), where a Mean Fluorescence Intensity (MFI) of 1000 is the positive threshold.
- •6.Patient is considered compliant and intends to be available for follow-up study period of 1 year.
- •7.Patient must have no known hypersensitivity to treatment with bortezomib, boron, or mannitol.
- •8.Patient must have no hypersensitivity to rituximab. 9.Patient must have no history of allergy or anaphylaxis to rabbit proteins or to any product excipients, or have active acute or chronic infections which contraindicate additional immunosuppression.
- •10.Patient must have no history of an anaphylactic or severe systemic response to Immune Globulin (Human). Individuals with selective IgA deficiencies who have antibody against IgA (anti-IgA antibody) should not receive IVIG since these patients may experience severe reactions to the IgA which may be present.
- •11.Patients without an AICD implanted will need to consent to wear a Zoll LifeVest Wearable Defibrillator.
排除标准
- •Women who are pregnant, breastfeeding, or have a positive pregnancy test on enrollment. If the patient becomes pregnant during the study, she must be removed from the study before receiving any additional study drug.
- •History of hepatitis C virus (HCV) positivity (by polymerase chain reaction, PCR)
- •Patients who are human immunodeficiency virus (HIV)-positive, or hepatitis B surface antigen (HBsAg)-positive.
- •Patient is deemed likely to have a second solid organ transplant or cell transplant (e.g. kidney or islet cell) in next 3 years.
- •Patient at risk for tuberculosis (TB):
- •Current clinical, radiographic, or laboratory evidence of active or latent TB as determined by local standard of care
- •History of active TB:
- •Within the last 2 years, even if treated
- •Greater than 2 years ago, unless there is documentation of adequate treatment according to locally accepted clinical practice
- •Patient at risk of reactivation of TB precludes administration of conventional immunosuppression (as determined by investigator and based upon appropriate evaluation)
- •Patient with active peptic ulcer disease (PUD), chronic diarrhea, or gastrointestinal malabsorption
- •Patient with a history of hypercoaguable state
- •Patient with hemoglobin < 7 g/dL, white blood cell (WBC) count < 2000/mm3 (3 x 109/L) or platelet count < 30,000 /mm3 prior to transplant
- •Receipt of a live vaccine within 4 weeks prior to study entry
- •Patient treated with immunosuppressive therapy (e.g. methotrexate, abatacept, etc) for indications such as autoimmune disease, or patient with comorbidity to a degree that treatment with such agents is likely during the trial in the opinion of the investigator
- •Patients with current or recent severe systemic infections within 2 weeks of medication start
- •Evidence of severe liver disease with abnormal liver profile (aspartate aminotransferase [AST], alanine aminotransferase [ALT] or total bilirubin > 1.5 times upper limit of normal (ULN) at screening.)
- •Patient has ≥ Grade 2 peripheral neuropathy within 14 days of medication start
- •History of malignancy within the past 5 years that is not considered to be cured, with the exception of localized basal cell carcinoma of the skin (excised ≥ 2 years prior to study initiation)
- •Prisoner or patient compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g. infectious disease) illness
- •Patient with a history of substance abuse (drugs or alcohol) within the past 6 months, or psychotic disorders that are not compatible with adequate study follow-up
- •Patient with a history of amiodarone exposure within three months.
- •Patient with a previous heart or other transplant
研究组 & 干预措施
Elimination of Immunologic Memory
A single arm 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. The intervention includes a protocol of Thymoglobulin, Rituximab, plasmapheresis and Bortezomib.
干预措施: Bortezomib, Thymoglobulin, Rituximab, Gamimune N, (IVIG), Plasmapheresis (Drug)
结局指标
主要结局
Percentage of Patients Who Suffer Mortality, a Serious Adverse Event, or Other Adverse Event During the Study Period
时间窗: 583 days
Percentage of study patients who experience a serious safety issue during the three phases of the study as measured by all cause mortality, serious adverse reactions and other adverse reactions.
Percentage of Patients Who Experience Grade 3 and Above Non-Hematologic Toxicities
时间窗: 583 days
Percentage of patients who experience of grade 3 and above non-hematologic toxicities as measured by the incidence of hypersensitivity reaction, fever, nausea and vomiting or dehydration during the study period.
The Percentage of Patients Who Experience Any Grade of Peripheral Neuropathy
时间窗: 583 days
The percentage of patients in the study who experience any grade of peripheral neuropathy during the study period
Percentage of Patients Who Experience CMV, PTLD, and PML
时间窗: 583 days
Percentage of patients who experience cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD), or progressive multifocal leukoencephalopathy (PML) during the study period.
Percentage of Patients With a Reduction in CPRA to Less Than 20%
时间窗: 365 days
Percentage of highly sensitized heart transplant candidates, (patients with a CPRA greater than 50%), who have desensitization therapy, and then achieve a reduction in alloantibody such that their CPRA falls below 20%. For an individual patient, the outcome measure time frame is the one year of the Recovery Phase which begins after 218 days from the time that the patient begins the Induction Immunotherapy Phase, which is the same as the end of the Bortezomib Treatment Phase.
Percentage of Patients Transplanted
时间窗: 365 days
Percentage of patients, who are transplanted within one year of finishing the Bortezomib treatment phase.
The Percentage of Patients Who Experience Either a Respiratory Tract Infection or a Urinary Tract Infection
时间窗: 583 days
The percentage of study patients who experience infectious complications in either the respiratory or urinary tracts during the study period.
The Percentage of Patients Who Experience Exacerbations Cardiac Dysrhythmias or Heart Failure
时间窗: 583 days
The percentage of study patients who experience an exacerbation of cardiac dysrhythmias and heart failure during the study period
Percentage of Patients With Grade 4 Hematologic Toxicities
时间窗: 583 days
A Grade 4 hematologic toxicity includes a platelet count \< 25,000/mm3 or an absolute neutrophil count \< 500/mm3
次要结局
- Percentage of Allograft Survival(730 days)
- The Percentage of Allografts That Endure Acute Rejection Within One Year of Transplantation(730 days)
- The Percentage of Patients With Antibody Mediated Rejection After Transplantation(730 days)
- Percentage of Patients Who Develop De Novo Alloantibody or DSA Alloantibody After Transplant(730 days)
- Percentage of Patients Post-Transplant That Are DSA Negative(730 days)
- Percentage of Patients With a CPRA <20%, But Were Not Transplanted During the Study Period(583 days)
- Percentage of Patients Who Receive Transplants Who Then Suffer Serious Post-transplant Complications(730 days)
研究者
Timothy Icenogle, MD
Director, Inland Northwest Thoracic Transplant Program
Providence Health & Services