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

This study has been terminated.
(Inability to enroll within funding period)
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01769443
First received: January 14, 2013
Last updated: October 14, 2015
Last verified: October 2015

January 14, 2013
October 14, 2015
June 2013
July 2014   (final data collection date for primary outcome measure)
Composite of Incidence of the Following Events in Subjects [ Time Frame: At transplant, or 90 days post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • 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.
Composite of Incidence of the Following Events in Subjects [ Time Frame: at transplant, or 90 days postrandomization, whichever occurs first ] [ Designated as safety issue: No ]
  • 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.
Complete list of historical versions of study NCT01769443 on ClinicalTrials.gov Archive Site
  • Time From Wait Listing to Heart Transplantation [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: No ]
  • Change in Calculated PRA (cPRA) From Wait Listing to Transplantation [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: No ]
  • Incidence of Death [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Incidence of Initiation of Any Mechanical Circulatory Support Device [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of Severe Infection Requiring Intravenous Antibiotics [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of Cerebral Vascular Accident [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of Acute Renal Failure Requiring Hemodialysis [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing. [ Time Frame: 24 and 52 weeks: ] [ Designated as safety issue: Yes ]
  • Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD) [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Death [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Re-transplantation or Re-listed for Transplantation [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: No ]
  • Incidence of Hospitalizations [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Incidence of Rejection Episodes Per Subject and Freedom From Rejection [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]

    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 from wait listing to transplantation. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: No ]
  • Change in Calculated PRA (cPRA) From Wait Listing to Transplantation [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: No ]
  • Incidence of death. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Incidence of Initiation of Any Mechanical Circulatory Support Device [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of severe infection requiring intravenous antibiotics. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of Cerebral Vascular Accident [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of Acute Renal Failure Requiring Hemodialysis [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Incidence of administering desensitization therapy beyond 90 days after randomization. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ] [ Designated as safety issue: Yes ]
  • Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Number of subjects on left ventricular assist devices (LVAD) compared to those not on LVADs. [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing. [ Time Frame: 24 and 52 weeks: ] [ Designated as safety issue: Yes ]
  • Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD) [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Death [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Re-transplantation or Re-listed for Transplantation [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: No ]
  • Incidence of Hospitalizations [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]
  • Incidence of Rejection Episodes Per Subject and Freedom From Rejection [ Time Frame: 24 and 52 weeks post-transplantation ] [ Designated as safety issue: Yes ]

    Rejection is defined 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).
Not Provided
Not Provided
 
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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Primary Heart Transplant
  • Heart Transplantation
  • Heart Transplant
  • 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 Name: 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 Name: apheresis (plasma)
  • 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.

    Interventions:
    • Drug: bortezomib
    • Procedure: plasmapheresis

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
2
July 2014
July 2014   (final data collection date for primary outcome measure)

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.
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01769443
DAIT CTOT-13, U01AI063594
Yes
Not Provided
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Trials in Organ Transplantation
Study Chair: Jon A Kobashigawa, MD Cedars-Sinai Heart Institute
Principal Investigator: Peter S. Heeger, MD Icahn School of Medicine at Mount Sinai
National Institute of Allergy and Infectious Diseases (NIAID)
October 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP