Clinical trial NCT01769443: Safety and Efficacy of Desensitization Therapy in Sensitized Participants Awaiting Heart Transplantation
Official title: A Prospective, Randomized, Multicenter, Two-Parallel Arm Study Evaluating the Overall Efficacy and Safety of Desensitization Therapy on Selected Patients Awaiting Heart Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Primary Heart Transplant
Heart Transplantation
Heart Transplant
Keywords: desensitization therapy
bortezomib (VELCADE®)
plasmapheresis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Clinical Trials in Organ Transplantation
First posted: 2013-01-16
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective is to evaluate the efficacy of desensitization therapy, which includes VELCADE® (bortezomib) and plasmapheresis, on select sensitized patients awaiting heart transplantation.

Detailed description: Bortezomib works by decreasing plasma cells in the blood. Plasma cells produce antibodies. Plasmapheresis is a procedure that removes antibodies from the blood. Plasma cells and antibodies produced by plasma cells can be involved in organ rejection after transplantation.

This trial will evaluate if decreasing plasma cells and antibodies with bortezomib and plasmapheresis can reduce complications while participants are waiting for their heart transplant. The evaluation of efficacy is defined by a lower complication rate while on the heart transplant waitlist.

Eligibility criteria: Inclusion Criteria:

* Subject must be able to understand and provide informed consent;
* Candidate (as recipient) for a primary heart transplant (single organ transplant);
* Calculated panel reactive antibody (cPRA) of greater than 30% with a threshold using mean fluorescent intensity (MFI) of 3,000 or standard fluorescence intensity (SFI) of 60,000;
* Status 1 (1A or 1B) enrollment and randomization to occur within 2 weeks after status 1 listing;
* Female subject is either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse;
* Male subjects, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse;
* Negative test for HIV (human immunodeficiency virus), HBsAg (hepatitis B surface antigen), HBcAb (hepatitis B core antibody), and HCV (hepatitis C virus) antibodies within 6 months prior to study entry.

Exclusion Criteria:

* Recipient of multiple solid organ or tissue transplants;
* Prior history of organ transplantation;
* Women of childbearing potential with a positive serum β-human chorionic gonadotropin (β-hCG) pregnancy test.Pregnancy testing is not required for postmenopausal or surgically sterilized women;
* Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow-up period;
* Subject has a hypersensitivity to VELCADE® (bortezomib), boron, or mannitol;
* Active systemic infection at time of enrollment;
* Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
* History of malignancy except when noted by an oncology specialist that tumor recurrence is low based on tumor type, response to therapy and negative metastatic work-up;
* Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy;
* Subjects with a platelet count of less than 75,000 within 7 days prior to enrollment;
* Subjects with an absolute neutrophil count (ANC) of less than 1,500 within 7 days prior to enrollment;
* Subjects with \>1.5 x ULN (upper limit of normal) total bilirubin;
* Subjects with any grade or history of neuropathy;
* Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements;
* Participation in another interventional clinical trial or requiring treatment using un-marketed investigational drug(s) within 14 days of start of this trial and throughout the duration of this trial.

Primary outcomes:
measure: Composite of Incidence of the Following Events in Subjects
timeFrame: At transplant, or 90 days post-randomization, whichever occurs first
Secondary outcomes:
measure: Time From Wait Listing to Heart Transplantation
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Change in Calculated PRA (cPRA) From Wait Listing to Transplantation
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Death
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Removal From Transplant Waiting List for Any Reason Except Improvement of Cardiac Function
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Initiation of Any Mechanical Circulatory Support Device
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Severe Infection Requiring Intravenous Antibiotics
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Cerebral Vascular Accident
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Acute Renal Failure Requiring Hemodialysis
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization
timeFrame: At transplant, or 1 year post-randomization, whichever occurs first
measure: Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year
timeFrame: 24 and 52 weeks post-transplantation
measure: Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy
timeFrame: 24 and 52 weeks post-transplantation
measure: Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs
timeFrame: 24 and 52 weeks post-transplantation
measure: Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing.
timeFrame: 24 and 52 weeks:
measure: Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD)
timeFrame: 24 and 52 weeks post-transplantation
measure: Death
timeFrame: 24 and 52 weeks post-transplantation
measure: Re-transplantation or Re-listed for Transplantation
timeFrame: 24 and 52 weeks post-transplantation
measure: Incidence of Hospitalizations
timeFrame: 24 and 52 weeks post-transplantation
measure: Incidence of Rejection Episodes Per Subject and Freedom From Rejection
timeFrame: 24 and 52 weeks post-transplantation
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Cedars Sinai Heart Institute
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Cedars-Sinai Heart Institute
name: Jon A Kobashigawa, MD
role: STUDY_CHAIR
affiliation: Icahn School of Medicine at Mount Sinai
name: Peter S. Heeger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: John R, Lietz K, Burke E, Ankersmit J, Mancini D, Suciu-Foca N, Edwards N, Rose E, Oz M, Itescu S. Intravenous immunoglobulin reduces anti-HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation. 1999 Nov 9;100(19 Suppl):II229-35. doi: 10.1161/01.cir.100.suppl_2.ii-229.
citation: Jordan SC, Vo A, Bunnapradist S, Toyoda M, Peng A, Puliyanda D, Kamil E, Tyan D. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003 Aug 27;76(4):631-6. doi: 10.1097/01.TP.0000080685.31697.FC.
citation: Leech SH, Lopez-Cepero M, LeFor WM, DiChiara L, Weston M, Furukawa S, Macha M, Singhal A, Wald JW, Nikolaidis LA, McClurken JB, Bove AA. Management of the sensitized cardiac recipient: the use of plasmapheresis and intravenous immunoglobulin. Clin Transplant. 2006 Jul-Aug;20(4):476-84. doi: 10.1111/j.1399-0012.2006.00509.x.
citation: McGee EC Jr, Cotts W, Tambur AR, Friedewald J, Kim J, O'Connell J, Wallace S, McCarthy PM. Successful bridge to transplant in a highly sensitized patient with a complicated pump pocket infection. J Heart Lung Transplant. 2008 May;27(5):568-71. doi: 10.1016/j.healun.2008.02.006.