Multi-Drug Desensitization Protocol for Heart Transplant Candidates

NCT01556347 | Terminated Phase 2 Results DMC

• 1 other identifier: IND110875
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Transplantation

Keywords

alloantibody; immunologic; memory; heart; transplant; desensitization

Outcome Measures

Primary Outcomes (9)

• Percentage of Patients With a Reduction in CPRA to Less Than 20%

  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.

  365 days

• Percentage of Patients Transplanted

  Percentage of patients, who are transplanted within one year of finishing the Bortezomib treatment phase.

  365 days

• Percentage of Patients Who Suffer Mortality, a Serious Adverse Event, or Other Adverse Event During the Study Period

  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.

  583 days

• Percentage of Patients Who Experience Grade 3 and Above Non-Hematologic Toxicities

  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.

  583 days

• The Percentage of Patients Who Experience Any Grade of Peripheral Neuropathy

  The percentage of patients in the study who experience any grade of peripheral neuropathy during the study period

  583 days

• Percentage of Patients Who Experience CMV, PTLD, and PML

  Percentage of patients who experience cytomegalovirus (CMV), post-transplant lymphoproliferative disease (PTLD), or progressive multifocal leukoencephalopathy (PML) during the study period.

  583 days

• The Percentage of Patients Who Experience Either a Respiratory Tract Infection or a Urinary Tract Infection

  The percentage of study patients who experience infectious complications in either the respiratory or urinary tracts during the study period.

  583 days

• The Percentage of Patients Who Experience Exacerbations Cardiac Dysrhythmias or Heart Failure

  The percentage of study patients who experience an exacerbation of cardiac dysrhythmias and heart failure during the study period

  583 days

• Percentage of Patients With Grade 4 Hematologic Toxicities

  A Grade 4 hematologic toxicity includes a platelet count \< 25,000/mm3 or an absolute neutrophil count \< 500/mm3

  583 days

Secondary Outcomes (7)

• 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 Allograft Survival

  730 days

• The Percentage of Allografts That Endure Acute Rejection Within One Year of Transplantation

  730 days

Study Arms (1)

Elimination of Immunologic Memory

EXPERIMENTAL

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

Interventions

Bortezomib, Thymoglobulin, Rituximab, Gamimune N, (IVIG), Plasmapheresis DRUG

Also known as: Anti-thymocyte globulin (rabbit), Rituxan, Velcade

Elimination of Immunologic Memory

Eligibility Criteria

• Age: 18 Years - 67 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.
• 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.
• Male subject agrees to use an acceptable method for contraception for the duration of the study.
• Patient is greater than or equal to 18 years of age but less than 70 years old (inclusive).
• 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.
• Patient is considered compliant and intends to be available for follow-up study period of 1 year.
• Patient must have no known hypersensitivity to treatment with bortezomib, boron, or mannitol.
• 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.
• 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.
• Patients without an AICD implanted will need to consent to wear a Zoll LifeVest Wearable Defibrillator.

You may not qualify if:

• 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

Sponsors & Collaborators

• Providence Health & Services: lead

Study Sites (1)

Providence Sacred Heart Medical Center

Spokane, Washington, 99204, United States

Location

MeSH Terms

Interventions

Bortezomib; thymoglobulin; Rituximab; Immunoglobulins, Intravenous; Plasmapheresis; Antilymphocyte Serum

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin G; Immunoglobulin Isotypes; Blood Component Removal; Therapeutics; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative; Immune Sera; Biological Products; Complex Mixtures

Limitations and Caveats

The Study was terminated because of lack of efficacy. One patient was transplanted after the study period ended and died postoperatively. Autopsy did not reveal evidence of antibody mediated rejection.

Results Point of Contact

• Title: Timothy B Icenogle MD
• Organization: Tim Icenogle MD PLLC

timicenogle@comcast.net

509-220-1900

Study Officials

• Tiimothy B Icenogle, MD

  Providence Sacred Heart Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Inland Northwest Thoracic Transplant Program

Study Record Dates

• First Submitted: March 15, 2012
• First Posted: March 16, 2012
• Study Start: July 1, 2012
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: June 15, 2018
• Results First Posted: June 15, 2018

Record last verified: 2018-06

Locations

US (1)