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Multi-Drug Desensitization Protocol for Heart Transplant Candidates

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ClinicalTrials.gov Identifier: NCT01556347
Recruitment Status : Terminated (Lack of efficacy)
First Posted : March 16, 2012
Results First Posted : June 15, 2018
Last Update Posted : June 15, 2018
Sponsor:
Information provided by (Responsible Party):
Timothy Icenogle, MD, Providence Health & Services

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Heart Transplantation Drug: Bortezomib, Thymoglobulin, Rituximab, Gamimune N, (IVIG), Plasmapheresis Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-Drug Desensitization Protocol for Heart Transplant Candidates
Study Start Date : July 2012
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Bortezomib, Thymoglobulin, Rituximab, Gamimune N, (IVIG), Plasmapheresis
Other Name: Anti-thymocyte globulin (rabbit), Rituxan, Velcade




Primary Outcome Measures :
  1. Percentage of Patients With a Reduction in CPRA to Less Than 20% [ Time Frame: 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.

  2. Percentage of Patients Transplanted [ Time Frame: 365 days ]
    Percentage of patients, who are transplanted within one year of finishing the Bortezomib treatment phase.

  3. Percentage of Patients Who Suffer Mortality, a Serious Adverse Event, or Other Adverse Event During the Study Period [ Time Frame: 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.

  4. Percentage of Patients Who Experience Grade 3 and Above Non-Hematologic Toxicities [ Time Frame: 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.

  5. The Percentage of Patients Who Experience Any Grade of Peripheral Neuropathy [ Time Frame: 583 days ]
    The percentage of patients in the study who experience any grade of peripheral neuropathy during the study period

  6. Percentage of Patients Who Experience CMV, PTLD, and PML [ Time Frame: 583 days ]
    Percentage of patients who experience cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD), or progressive multifocal leukoencephalopathy (PML) during the study period.

  7. The Percentage of Patients Who Experience Either a Respiratory Tract Infection or a Urinary Tract Infection [ Time Frame: 583 days ]
    The percentage of study patients who experience infectious complications in either the respiratory or urinary tracts during the study period.

  8. The Percentage of Patients Who Experience Exacerbations Cardiac Dysrhythmias or Heart Failure [ Time Frame: 583 days ]
    The percentage of study patients who experience an exacerbation of cardiac dysrhythmias and heart failure during the study period

  9. Percentage of Patients With Grade 4 Hematologic Toxicities [ Time Frame: 583 days ]
    A Grade 4 hematologic toxicity includes a platelet count < 25,000/mm3 or an absolute neutrophil count < 500/mm3


Secondary Outcome Measures :
  1. The Percentage of Patients With Antibody Mediated Rejection After Transplantation [ Time Frame: 730 days ]
    The percentage of patients who experience antibody mediated rejection at 6 months and 1 year post transplant. The study period was 583 days, during which a patient was eligible for transplant during the last 365 days. If a patient was transplanted on day 583, then the patient is followed for one year after the transplant, then the total time to assess the two patients would have been a period of two years or 730 days. In fact, neither patient was transplanted within the study period.

  2. Percentage of Patients Who Develop De Novo Alloantibody or DSA Alloantibody After Transplant [ Time Frame: 730 days ]
    Percentage of patients who are transplanted with the study period who then develop de novo or donor-specific alloantibody (DSA) within one year post-transplant. The patients would be eligible for transplant after day 218 in the study protocol and the study had 365 days in which to be transplanted. If a patient was transplant on day 583,( the last day of eligibility), and then followed for one year, then the outcome time frame would be a total of two years. No patient was transplanted within the study period.

  3. Percentage of Patients Post-Transplant That Are DSA Negative [ Time Frame: 730 days ]
    Percentage of patients who receive a transplant within the study period who are then DSA negative at 1 year following transplantation.

  4. Percentage of Allograft Survival [ Time Frame: 730 days ]
    The percentage of allografts transplanted during the study period that survive to 6 and 12 months post transplant.

  5. The Percentage of Allografts That Endure Acute Rejection Within One Year of Transplantation [ Time Frame: 730 days ]
    The percentage of allografts that have an acute rejection episode per the criteria of the International Society of Heart and Lung Transplantation (ISHLT) within one year of transplantation. Allografts implanted during the Recovery Phase are monitored for a year for acute rejection per the study protocol. An allograft potentially implanted on the last day of a patient's recovery period would still be monitored for a year, so the potential outcome measure time would be 730 days. Since no allografts were implanted during the recovery period, there are no results to report.

  6. Percentage of Patients With a CPRA <20%, But Were Not Transplanted During the Study Period [ Time Frame: 583 days ]
    Proportion of patients who achieve a Calculated Panel Reactive Antibody test CPRA of < 20%, but are not transplanted within the study period.

  7. Percentage of Patients Who Receive Transplants Who Then Suffer Serious Post-transplant Complications [ Time Frame: 730 days ]
    Percentage of study patients who receive transplants within the study period who then experience 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) within 1 year of transplantation.



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Ages Eligible for Study:   18 Years to 67 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. 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.

Exclusion Criteria:

  1. 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.
  2. History of hepatitis C virus (HCV) positivity (by polymerase chain reaction, PCR)
  3. Patients who are human immunodeficiency virus (HIV)-positive, or hepatitis B surface antigen (HBsAg)-positive.
  4. Patient is deemed likely to have a second solid organ transplant or cell transplant (e.g. kidney or islet cell) in next 3 years.
  5. Patient at risk for tuberculosis (TB):

    1. Current clinical, radiographic, or laboratory evidence of active or latent TB as determined by local standard of care
    2. History of active TB:
    3. Within the last 2 years, even if treated
    4. Greater than 2 years ago, unless there is documentation of adequate treatment according to locally accepted clinical practice
    5. Patient at risk of reactivation of TB precludes administration of conventional immunosuppression (as determined by investigator and based upon appropriate evaluation)
  6. Patient with active peptic ulcer disease (PUD), chronic diarrhea, or gastrointestinal malabsorption
  7. Patient with a history of hypercoaguable state
  8. 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
  9. Receipt of a live vaccine within 4 weeks prior to study entry
  10. 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
  11. Patients with current or recent severe systemic infections within 2 weeks of medication start
  12. 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.)
  13. Patient has ≥ Grade 2 peripheral neuropathy within 14 days of medication start
  14. 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)
  15. Prisoner or patient compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g. infectious disease) illness
  16. 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
  17. Patient with a history of amiodarone exposure within three months.
  18. Patient with a previous heart or other transplant

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01556347


Locations
United States, Washington
Providence Sacred Heart Medical Center
Spokane, Washington, United States, 99204
Sponsors and Collaborators
Providence Health & Services
Investigators
Principal Investigator: Tiimothy B Icenogle, MD Providence Sacred Heart Medical Center

Responsible Party: Timothy Icenogle, MD, Director, Inland Northwest Thoracic Transplant Program, Providence Health & Services
ClinicalTrials.gov Identifier: NCT01556347     History of Changes
Other Study ID Numbers: IND110875
First Posted: March 16, 2012    Key Record Dates
Results First Posted: June 15, 2018
Last Update Posted: June 15, 2018
Last Verified: June 2018

Keywords provided by Timothy Icenogle, MD, Providence Health & Services:
alloantibody
immunologic
memory
heart
transplant
desensitization

Additional relevant MeSH terms:
Rituximab
Bortezomib
Thymoglobulin
Antilymphocyte Serum
Immunoglobulins, Intravenous
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents