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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Primary Heart Transplant, Heart Transplantation, Heart Transplant

Intervention / Treatment
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* Drug: bortezomib
* Procedure: plasmapheresis


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No Desensitization Therapy<br>Subject(s) randomized to no desensitization therapy pre-transplant. | |
| Experimental: Desensitization Therapy<br>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<br>* 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.<br>* Other names: VELCADE®;Procedure: plasmapheresis<br>* 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.<br>* Other names: apheresis (plasma);|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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plasmapheresis, desensitization therapy, bortezomib (VELCADE®)