Multi-Drug Desensitization Protocol for Heart Transplant Candidates

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Providence Health & Services
Sponsor:
Information provided by (Responsible Party):
Timothy Icenogle, MD, Providence Health & Services
ClinicalTrials.gov Identifier:
NCT01556347
First received: March 15, 2012
Last updated: November 11, 2013
Last verified: November 2013
  Purpose

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 Intervention Phase
Alloantibodies
Heart Transplantation
Immunologic Memory
Drug: Bortezomib, Thymoglobulin, (rATG), Rituximab, Gamimune N, (IVIG), Plasmapheresis (Multidrug Protocol)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Multi-Drug Desensitization Protocol for Heart Transplant Candidates

Resource links provided by NLM:


Further study details as provided by Providence Health & Services:

Primary Outcome Measures:
  • Anti-HLA alloantibody reduction [ Time Frame: 218 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Proportion of patients, who are transplanted within one year of finishing desensitization therapy.

  • Overall Safety [ Time Frame: Six years ] [ Designated as safety issue: Yes ]
    Overall safety of combined immunotherapy with rATG, rituximab, IVIG, and bortezomib

  • Grade 3 Non-Hematologic Toxicities [ Time Frame: 583 days ] [ Designated as safety issue: Yes ]
    Incidence of grade 3 and above non-hematologic toxicities

  • Peripheral Neuropathy [ Time Frame: 583 days ] [ Designated as safety issue: Yes ]
    Incidence of all grades of peripheral neuropathy

  • CMV, PTLD, and PML [ Time Frame: Six years ] [ Designated as safety issue: Yes ]
    Incidence of cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD) and progressive multifocal leukoencephalopathy (PML)

  • Infection [ Time Frame: 583 days ] [ Designated as safety issue: Yes ]
    Incidence of infection complication

  • Cardiac Dysrhythmias and Heart Failure [ Time Frame: 583 days ] [ Designated as safety issue: Yes ]
    Incidence of exacerbation of cardiac dysrhythmias and heart failure


Secondary Outcome Measures:
  • Antibody Mediated Rejection [ Time Frame: Six years ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Proportion of patients who are DSA negative at 1 year following transplantation

  • Allograft survival [ Time Frame: Six years ] [ Designated as safety issue: Yes ]
    Allograft survival at 67 and 12 months post transplant

  • Acute Rejection [ Time Frame: Six years ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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


Estimated Enrollment: 20
Study Start Date: July 2012
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 67 Years
Genders Eligible for Study:   Both
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01556347

Contacts
Contact: Timothy B Icenogle, MD 509-623-7575 timicenogle@comcast.net
Contact: Alexa A Schmitt, PhD 509-474-2063 alexa.schmitt@providence.org

Locations
United States, Washington
Providence Sacred Heart Medical Center Recruiting
Spokane, Washington, United States, 99204
Contact: Timothy B Icenogle, MD    509-623-7575    timicenogle@comcast.net   
Contact: Alexa B Schmidt, PhD    509-474-2041      
Principal Investigator: Timothy B Icenogle, MD         
Sponsors and Collaborators
Providence Health & Services
Investigators
Principal Investigator: Tiimothy B Icenogle, MD Providence Sacred Heart Medical Center
  More Information

No publications provided

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
Study First Received: March 15, 2012
Last Updated: November 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Providence Health & Services:
alloantibody
immunologic
memory
heart
transplant
desensitization

Additional relevant MeSH terms:
Bortezomib
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014