Status:Not yet recruiting
Keywords:desensitization therapy , heart transplant , plasmapheresis , Velcade , antibody , antibody specificity , HLA typing , cPRA , Rejection
We hypothesize that administering desensitization therapy that includes VELCADE® (bortezomib) in sensitized patients awaiting heart transplant will result in lower antibody levels which will decrease morbidity and mortality while waiting, decrease time on the wait list for transplant and improve outcomes of subjects post-transplantation.
Primary Objective and Endpoint
The primary objective is to evaluate the efficacy of desensitization therapy, which includes VELCADE® (bortezomib) and plasmapheresis, on select sensitized patients awaiting heart transplantation. The evaluation of efficacy is defined by a lower complication rate while on the heart transplant waitlist.
The primary endpoint is a composite of incidence of the following events at transplant, or 90 days post-randomization, whichever occurs first:
• 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.
Secondary Clinical Objectives and Endpoints
Secondary Clinical Objectives
The secondary objective is to determine if desensitization therapy for the sensitized patient decreases pre-transplant morbidity and mortality on the waiting list and improves post-transplant outcomes.
Secondary Clinical Endpoints
Secondary Clinical Endpoints (Pre-Transplant Phase)
The following individual secondary clinical endpoints will be assessed at transplant, or 1 year post-randomization, whichever occurs first:
1. Time from wait listing to transplantation.
2. Change in calculated PRA (cPRA) from wait listing to transplantation.
3. Incidence of death.
4. Incidence of removal from transplant waiting list for any reason except improvement of cardiac function.
5. Incidence of initiation of any mechanical circulatory support device,
6. Incidence of severe infection requiring intravenous antibiotics.
7. Incidence of cerebral vascular accident.
8. Incidence of acute renal failure requiring hemodialysis.
9. Incidence of administering desensitization therapy beyond 90 days after randomization.
Secondary Clinical Endpoints (Post-Transplant Phase)
The post-transplant secondary clinical endpoints will include data that was collected as part of standard of care at the local center.
The following secondary clinical endpoints will be assessed at 24 and 52 weeks:
1. Post-transplant outcomes;
b. Re-transplantation or re-listed for transplantation,
c. Incidence of hospitalizations,
d. Incidence of rejection episodes per subject and freedom from rejection as follows:
• Biopsy proven acute rejection (BPAR) of any grade (cellular rejection per 2004 ISHLT grading scale),
• BPAR (individual grades),
• BPAR > 2R
• antibody mediated rejection (AMR),
• Any treated rejection,
• Rejection associated with hemodynamic compromise (HDC).
2. Development of angiographically evident cardiac allograft vasculopathy at 1 year;
3. Post-transplant safety outcomes including;
a. Incidence of serious infections requiring intravenous antimicrobial therapy,
b. Incidence of PTLD
4. Number of subjects on left ventricular assist devices (LVAD) compared to those not on LVADs.
5. Cardiac dysfunction as reflected in the left ventricular ejection fractions < 40% by echocardiography or, angiogram.
Secondary Mechanistic Objectives and Endpoints
Secondary Mechanistic Objectives
The objective of the mechanistic studies is to determine the effects of VELCADE® (bortezomib) on the humoral, molecular, and cellular alloimmune response during and after desensitization therapy.
1. To determine the effect of desensitization on class I and class II HLA antibody titer and antibody specificity.
2. To determine the effect of desensitization on antibody heavy chain immunoglobulin class switch of anti-HLA antibodies
3. To determine the effect of desensitization on the capacity of anti-HLA antibodies to fix complement by measuring C1q binding.
4. To determine the effect of desensitization on the frequencies and cytokine profiles of direct and indirect alloreactive T cells.
5. To define the peripheral blood molecular transcriptional signature associated with proteasome inhibition and to assess the relationship of these effects to the changes in alloimmunity.
6. To determine the effect of desensitization on serum cytokines and chemokines involved in B cell regulation and reconstitution, and to assess the relationship of these effects to the changes in alloimmunity.
7. To determine the effects of desensitization on the phenotype of peripheral blood cells including T cells, B cells, NK/NKT cells and dendritic cells. and to assess the relationship of these effects to the changes in alloimmunity.
8. To determine the relationships between graft tissue gene expression, graft tissue complement deposition, graft tissue complement regulator expression and the histologic phenotype of rejection
Secondary Mechanistic Endpoints (Pre-Transplant Phase)
Endpoints are comparisons of effects on each parameter between study randomization and the time of transplantation (or reaching the study endpoint) comparing the group given desensitization to controls (no desensitization).
1. Change in pre-transplant HLA antibody titer.
2. Change in antibody specificity.
3. Change in antibody isotype.
4. Change in antibody complement binding (C1q binding).
5. Change in serum cytokines/chemokines.
6. Change in frequency and cytokine profile of alloreactive T cells.
7. Change in molecular profile of peripheral blood mononuclear cell RNA.
8. Change in percentage of peripheral blood naïve B cells, memory B cells, transitional B cells, plasmablasts, and plasma cells.
Secondary Mechanistic Endpoints (Post-Transplant Phase)
1. Change in donor reactive and total antibody titer, specificity, isotype and complement binding capacity between time of transplantation and 52 weeks post-transplant
2. Change in alloreactive T cell immunity between time of transplantation and 52 weeks post-transplant
3. The strength of the relationship between HLA Ab Class I and II, donor specific antibodies and AMR
4. The strength of the relationship between HLA Ab Class I and II, donor specific antibodies and CAV at 52 weeks
5. The strength of the relationship between T cell alloimmunity and AMR
6. The strength of the relationship between T cell alloimmunity and CAV at 52 weeks
7. The strength of the relationship between serum cytokines and AMR
8. The strength of the relationship between serum cytokines and CAV at 52 weeks
9. The strength of the relationship between molecular profiles of PBMC and AMR
10. The strength of the relationship between molecular profiles of PBMC and CAV at 52 weeks
11. The strength of the relationship between Immunophenotyping and AMR
12. The strength of the relationship between Immunophenotyping and CAV at 52 weeks
13. Histological changes of Chronic Acute Rejection and Antibody Mediated Rejection
This is a prospective, multi-center, randomized, un-blinded, two parallel group clinical trial in which 80 patients awaiting primary heart transplant will be randomized (1:1) to no desensitization therapy pre-transplant versus desensitization therapy consisting of plasmapheresis with concomitant VELCADE® (bortezomib). Subjects will be enrolled at the time of wait listing for transplant and those eligible subjects with local cPRA between 40-70% inclusive will be randomized to the two pre-transplant treatment arms, otherwise they will be terminated from the study. Randomized subjects will be assessed for the primary endpoint pre-transplant and those dying or de-listed will be terminated at that time. Subjects going on to transplant will be treated by standard of care and assessed for post-transplant secondary endpoints at 24 and 52 weeks post-transplant. Subjects not transplanted will be terminated.
RATIONALE FOR SELECTION OF STUDY POPULATION
Heart transplant candidates will be screened, consented and randomized within 2 weeks from the time of listing as status 1 on the heart transplant waiting list. Status 1 patients have a relatively shorter time to transplant (weeks to months) compared to status 2 patients who can wait for years. Using only status 1 patients will allow assessment of data within the time period of this study. In addition, it is these status 1 patients that are at greatest risk for morbidity and mortality (while waiting on the list) which will be included as endpoints in this study. The study is designed to determine the efficacy of desensitization in heart transplant candidates. Patients will be randomized to therapy or no therapy. The status 1 heart transplant candidates will be screened to determine their cPRA and only those with values between 40% and 70% will be eligible for randomization. The effects of desensitization in these patients are unknown. Patients with cPRA <40% are highly likely to receive a heart transplant and thus unlikely to benefit from desensitization. Patients with cPRA >70% are unlikely to receive a heart transplant without desensitization raising ethical issues about withholding therapy.
Patients who meet all of the following criteria are eligible for enrollment as study subjects:
1. Subject must be able to understand and provide informed consent;
2. Male or Female, >18 years of age;
3. Candidate for a primary heart transplant recipient (single organ transplant);
4. cPRA of 40% to 70% with a threshold using MFI of 3,000 or SFI of 60,000 (Local HLA Center);
5. Status 1 (1A or 1B) at the time of listing (listing to occur within 2 weeks prior to enrollment);
6. 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.
7. 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.
8. Negative test for HIV, HBsAg, HBcAb, and HCV Ab within 6 months prior to study entry.
Patients who meet any of these criteria are not eligible for enrollment as study subjects:
1. Recipient of multiple solid organ or tissue transplants;
2. Prior history of organ transplantation;
3. 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;
4. Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow-up period;
5. Patient has a hypersensitivity to VELCADE® (bortezomib), boron, or mannitol;
6. Active systemic infection at time of enrollment;
7. Any history of Serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
8. 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;
9. 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;
10. Patients with a platelet count of less than 75,000 within 7 days prior to enrollment;
11. Patients with an absolute neutrophil count of less than 1,500 within 7 days prior to enrollment;
12. Patients with >1.5 x ULN Total Bilirubin;
13. Patients with any grade or history of neuropathy;
14. Any condition that, in the opinion of the investigator, would interfere with the subject’s ability to comply with study requirements;
15. Participation in another interventional clinical trial or requiring treatment using an un-marketed investigational drugs within 14 days of start of this trial and throughout the duration of this trial.