Multi-Drug Desensitization Protocol for Heart Transplant Candidates

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01556347
Recruitment Status : Terminated (Lack of efficacy)
First Posted : March 16, 2012
Last Update Posted : December 23, 2016
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, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis (Multidrug Protocol) 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

Drug Information available for: Bortezomib
U.S. FDA Resources

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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.

  2. Proportion of Transplanted Patients [ Time Frame: Six years ]
    Proportion of patients, who are transplanted within one year of finishing desensitization therapy.

  3. Overall Safety [ Time Frame: Six years ]
    Overall safety of combined immunotherapy with rATG, rituximab, IVIG, and bortezomib

  4. Grade 3 Non-Hematologic Toxicities [ Time Frame: 583 days ]
    Incidence of grade 3 and above non-hematologic toxicities

  5. Peripheral Neuropathy [ Time Frame: 583 days ]
    Incidence of all grades of peripheral neuropathy

  6. CMV, PTLD, and PML [ Time Frame: Six years ]
    Incidence of cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD) and progressive multifocal leukoencephalopathy (PML)

  7. Infection [ Time Frame: 583 days ]
    Incidence of infection complication

  8. Cardiac Dysrhythmias and Heart Failure [ Time Frame: 583 days ]
    Incidence of exacerbation of cardiac dysrhythmias and heart failure

Secondary Outcome Measures :
  1. Antibody Mediated Rejection [ Time Frame: Six years ]
    Incidence of antibody mediated rejection at 6 months and 1 year post transplant

  2. 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

  3. DSA Negative Patients Post-Transplant [ Time Frame: Six years ]
    Proportion of patients who are DSA negative at 1 year following transplantation

  4. Allograft survival [ Time Frame: Six years ]
    Allograft survival at 67 and 12 months post transplant

  5. 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

  6. 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.

  7. 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

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

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 identifier (NCT number): NCT01556347

United States, Washington
Providence Sacred Heart Medical Center
Spokane, Washington, United States, 99204
Sponsors and Collaborators
Providence Health & Services
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 Identifier: NCT01556347     History of Changes
Other Study ID Numbers: IND110875
First Posted: March 16, 2012    Key Record Dates
Last Update Posted: December 23, 2016
Last Verified: December 2016

Keywords provided by Timothy Icenogle, MD, Providence Health & Services:

Additional relevant MeSH terms:
Immunoglobulins, Intravenous
Rho(D) Immune Globulin
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents