Safety and Efficacy of Desensitization Therapy in Sensitized Participants Awaiting Heart Transplantation

A Prospective, Randomized, Multicenter, Two-Parallel Arm Study Evaluating the Overall Efficacy and Safety of Desensitization Therapy on Selected Patients Awaiting Heart Transplantation

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

Study Overview

• Status: Terminated
• Conditions: Heart Transplantation; Heart Transplant; Primary Heart Transplant
• Intervention / Treatment: Drug: bortezomib; Procedure: plasmapheresis

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars Sinai Heart Institute
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
  • Utah
    • Murray, Utah, United States, 84157
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No Desensitization Therapy; Subject(s) randomized to no desensitization therapy pre-transplant.
Experimental: Desensitization Therapy; Subject(s) randomized to desensitization therapy pre-transplant. Desensitization therapy regimen pre-transplant: Plasmapheresis for 3 consecutive days (treatment days 0, 1 and 2) followed by concomitant bortezomib dosed at 1.3 mg/m^2 as a 3 to 5 second bolus intravenous injection on treatment days 0, 3, 7 and 10. The first dose of bortezomib is administered between 4-8 hours after the first plasmapheresis session is completed and there must be at least 96 hours between the second and third dose of bortezomib.	Drug: bortezomib; Bortezomib dosed at 1.3 mg/m^2 as a 3 to 5 second bolus administered by intravenous injection on treatment days 0, 3, 7 and 10. The first dose of bortezomib is administered between 4-8 hours after the first plasmapheresis session is completed and there must be at least 96 hours between the second and third dose of bortezomib.; Other Names: VELCADE®; Procedure: plasmapheresis; Plasmapheresis for 3 consecutive days (treatment days 0, 1 and 2) followed by concomitant bortezomib dosed at 1.3 mg/m^2 as a 3 to 5 second bolus administered by intravenous injection on treatment days 0, 3, 7 and 10. The first dose of bortezomib is administered between 4-8 hours after the first plasmapheresis session is completed and there must be at least 96 hours between the second and third dose of bortezomib.; Other Names: apheresis (plasma)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Incidence of the Following Events in Subjects	Death,; Removal from the transplant waiting list for any reason except improvement of cardiac function,; Initiation of any mechanical circulatory support device,; Severe infection requiring intravenous antibiotics,; Cerebral vascular accident,; Acute renal failure requiring dialysis.	At transplant, or 90 days post-randomization, whichever occurs first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From Wait Listing to Heart Transplantation		At transplant, or 1 year post-randomization, whichever occurs first
Change in Calculated PRA (cPRA) From Wait Listing to Transplantation		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Death		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Removal From Transplant Waiting List for Any Reason Except Improvement of Cardiac Function		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Initiation of Any Mechanical Circulatory Support Device		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Severe Infection Requiring Intravenous Antibiotics		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Cerebral Vascular Accident		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Acute Renal Failure Requiring Hemodialysis		At transplant, or 1 year post-randomization, whichever occurs first
Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization		At transplant, or 1 year post-randomization, whichever occurs first
Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year		24 and 52 weeks post-transplantation
Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy		24 and 52 weeks post-transplantation
Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs		24 and 52 weeks post-transplantation
Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing.		24 and 52 weeks:
Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD)		24 and 52 weeks post-transplantation
Death		24 and 52 weeks post-transplantation
Re-transplantation or Re-listed for Transplantation		24 and 52 weeks post-transplantation
Incidence of Hospitalizations		24 and 52 weeks post-transplantation
Incidence of Rejection Episodes Per Subject and Freedom From Rejection	Rejection is defined as follows: Biopsy proven acute rejection (BPAR) of any grade (cellular rejection per 2004 ISHLT [International Society of Heart and Lung Transplantation] grading scale),; BPAR (individual grades),; BPAR (Biopsy Proven Acute Rejection) > 2R; antibody mediated rejection (AMR),; Any treated rejection,; Rejection associated with hemodynamic compromise (HDC).	24 and 52 weeks post-transplantation

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Clinical Trials in Organ Transplantation
• Investigators: Study Chair: Jon A Kobashigawa, MD, Cedars-Sinai Heart Institute

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Clinical Trials in Organ Transplantation (CTOT)

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: January 14, 2013
• First Submitted That Met QC Criteria: January 14, 2013
• First Posted (Estimate): January 16, 2013

Study Record Updates

• Last Update Posted (Estimate): November 11, 2015
• Last Update Submitted That Met QC Criteria: October 14, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: desensitization therapy; plasmapheresis; bortezomib (VELCADE®)
• Additional Relevant MeSH Terms: Antineoplastic Agents; Bortezomib
• Other Study ID Numbers: DAIT CTOT-13; U01AI063594 (U.S. NIH Grant/Contract)