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

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ClinicalTrials.gov Identifier: NCT01769443
Recruitment Status : Terminated (Inability to enroll within funding period)
First Posted : January 16, 2013
Results First Posted : November 11, 2015
Last Update Posted : November 11, 2015
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE January 14, 2013
First Posted Date  ICMJE January 16, 2013
Results First Submitted Date  ICMJE October 13, 2015
Results First Posted Date  ICMJE November 11, 2015
Last Update Posted Date November 11, 2015
Study Start Date  ICMJE June 2013
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 14, 2015)
Composite of Incidence of the Following Events in Subjects [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 14, 2013)
Composite of Incidence of the Following Events in Subjects [ Time Frame: at transplant, or 90 days postrandomization, 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 14, 2015)
  • Time From Wait Listing to Heart Transplantation [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Change in Calculated PRA (cPRA) From Wait Listing to Transplantation [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Death [ Time Frame: 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 [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Initiation of Any Mechanical Circulatory Support Device [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Severe Infection Requiring Intravenous Antibiotics [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Cerebral Vascular Accident [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Acute Renal Failure Requiring Hemodialysis [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing. [ Time Frame: 24 and 52 weeks: ]
  • Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD) [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Death [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Re-transplantation or Re-listed for Transplantation [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Incidence of Hospitalizations [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Incidence of Rejection Episodes Per Subject and Freedom From Rejection [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2013)
  • Time from wait listing to transplantation. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Change in Calculated PRA (cPRA) From Wait Listing to Transplantation [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of death. [ Time Frame: 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 [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Initiation of Any Mechanical Circulatory Support Device [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of severe infection requiring intravenous antibiotics. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Cerebral Vascular Accident [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of Acute Renal Failure Requiring Hemodialysis [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Incidence of administering desensitization therapy beyond 90 days after randomization. [ Time Frame: At transplant, or 1 year post-randomization, whichever occurs first ]
  • Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Number of subjects on left ventricular assist devices (LVAD) compared to those not on LVADs. [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing. [ Time Frame: 24 and 52 weeks: ]
  • Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD) [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Death [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Re-transplantation or Re-listed for Transplantation [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Incidence of Hospitalizations [ Time Frame: 24 and 52 weeks post-transplantation ]
  • Incidence of Rejection Episodes Per Subject and Freedom From Rejection [ Time Frame: 24 and 52 weeks post-transplantation ]
    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).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Desensitization Therapy in Sensitized Participants Awaiting Heart Transplantation
Official Title  ICMJE A Prospective, Randomized, Multicenter, Two-Parallel Arm Study Evaluating the Overall Efficacy and Safety of Desensitization Therapy on Selected Patients Awaiting Heart Transplantation
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Heart Transplant
  • Heart Transplantation
  • Heart Transplant
Intervention  ICMJE
  • 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)
Study Arms  ICMJE
  • 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
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 15, 2014)
2
Original Estimated Enrollment  ICMJE
 (submitted: January 14, 2013)
80
Actual Study Completion Date  ICMJE July 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01769443
Other Study ID Numbers  ICMJE DAIT CTOT-13
U01AI063594 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Clinical Trials in Organ Transplantation
Investigators  ICMJE
Study Chair: Jon A Kobashigawa, MD Cedars-Sinai Heart Institute
Principal Investigator: Peter S. Heeger, MD Icahn School of Medicine at Mount Sinai
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date October 2015

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