Heart Transplant, Heart Transplantation, Primary Heart Transplant
Conditions
Keywords
desensitization therapy, bortezomib (VELCADE®), plasmapheresis
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.
Interventions
DRUGbortezomib
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.
PROCEDUREplasmapheresis
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.
Sponsors
Clinical Trials in Organ Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Incidence of the Following Events in Subjects | At transplant, or 90 days post-randomization, whichever occurs first | * 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Time From Wait Listing to Heart Transplantation | At transplant, or 1 year post-randomization, whichever occurs first | — |
| 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 | 24 and 52 weeks post-transplantation | 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). |
| Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year | 24 and 52 weeks post-transplantation | — |
Countries
United States
Participant flow
Recruitment details
The study planned to enroll 80 participants; however, the decision to terminate the study was made due to the very slow rate of participant accrual and the inability to meet the recruitment goal within the funding period. Only 2 participants were enrolled at one site before study recruitment status changed to Active, not recruiting.
Participants by arm
| Arm | Count |
|---|---|
| No Desensitization No desensitization therapy pre-transplantation | 1 |
| Desensitization Plasmapheresis with concomitant bortezomib.
* Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient.
* Four doses of bortezomib (1.3 mg/m\^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib | 1 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study closure | 1 | 0 |
Baseline characteristics
| Characteristic | Total | No Desensitization | Desensitization |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 2 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
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.
Time frame: At transplant, or 90 days post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing.
Time frame: 24 and 52 weeks:
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Change in Calculated PRA (cPRA) From Wait Listing to Transplantation
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Death
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Acute Renal Failure Requiring Hemodialysis
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Cerebral Vascular Accident
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Death
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Hospitalizations
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Initiation of Any Mechanical Circulatory Support Device
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD)
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
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).
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Removal From Transplant Waiting List for Any Reason Except Improvement of Cardiac Function
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Incidence of Severe Infection Requiring Intravenous Antibiotics
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Re-transplantation or Re-listed for Transplantation
Time frame: 24 and 52 weeks post-transplantation
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
Time From Wait Listing to Heart Transplantation
Time frame: At transplant, or 1 year post-randomization, whichever occurs first
Population: No analyses were performed due to slow enrollment and early study closure.