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

Heart Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01769443
• Other study ID #: DAIT CTOT-13
• Secondary ID: U01AI063594
• Status: Terminated
• Phase: Phase 2
• First received: January 14, 2013
• Last updated: October 14, 2015
• Start date: June 2013
• Est. completion date: July 2014

Study information

• Verified date: October 2015
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 ß-human chorionic gonadotropin (ß-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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Transplant
• Heart Transplantation
• Primary Heart Transplant

Intervention

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.

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.

Locations

Country	Name	City	State
United States	Cedars Sinai Heart Institute	Beverly Hills	California
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	The Methodist Hospital	Houston	Texas
United States	Minneapolis Heart Institute	Minneapolis	Minnesota
United States	Intermountain Medical Center	Murray	Utah
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Mount Sinai School of Medicine	New York	New York
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Utah	Salt Lake City	Utah
United States	University of California at San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Clinical Trials in Organ Transplantation

Country where clinical trial is conducted

United States, 

References & Publications (4)

John R, Lietz K, Burke E, Ankersmit J, Mancini D, Suciu-Foca N, Edwards N, Rose E, Oz M, Itescu S. Intravenous immunoglobulin reduces anti-HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation. 1999 Nov 9;100(19 Suppl):II229-35. — View Citation

Jordan SC, Vo A, Bunnapradist S, Toyoda M, Peng A, Puliyanda D, Kamil E, Tyan D. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003 Aug 27;76(4):631-6. — View Citation

Leech SH, Lopez-Cepero M, LeFor WM, DiChiara L, Weston M, Furukawa S, Macha M, Singhal A, Wald JW, Nikolaidis LA, McClurken JB, Bove AA. Management of the sensitized cardiac recipient: the use of plasmapheresis and intravenous immunoglobulin. Clin Transplant. 2006 Jul-Aug;20(4):476-84. — View Citation

McGee EC Jr, Cotts W, Tambur AR, Friedewald J, Kim J, O'Connell J, Wallace S, McCarthy PM. Successful bridge to transplant in a highly sensitized patient with a complicated pump pocket infection. J Heart Lung Transplant. 2008 May;27(5):568-71. doi: 10.1016/j.healun.2008.02.006. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	At transplant, or 90 days post-randomization, whichever occurs first	Yes
Secondary	Time From Wait Listing to Heart Transplantation		At transplant, or 1 year post-randomization, whichever occurs first	No
Secondary	Change in Calculated PRA (cPRA) From Wait Listing to Transplantation		At transplant, or 1 year post-randomization, whichever occurs first	No
Secondary	Incidence of Death		At transplant, or 1 year post-randomization, whichever occurs first	Yes
Secondary	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	Yes
Secondary	Incidence of Initiation of Any Mechanical Circulatory Support Device		At transplant, or 1 year post-randomization, whichever occurs first	Yes
Secondary	Incidence of Severe Infection Requiring Intravenous Antibiotics		At transplant, or 1 year post-randomization, whichever occurs first	Yes
Secondary	Incidence of Cerebral Vascular Accident		At transplant, or 1 year post-randomization, whichever occurs first	Yes
Secondary	Incidence of Acute Renal Failure Requiring Hemodialysis		At transplant, or 1 year post-randomization, whichever occurs first	Yes
Secondary	Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization		At transplant, or 1 year post-randomization, whichever occurs first	Yes
Secondary	Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year		24 and 52 weeks post-transplantation	Yes
Secondary	Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy		24 and 52 weeks post-transplantation	Yes
Secondary	Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs		24 and 52 weeks post-transplantation	Yes
Secondary	Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing.		24 and 52 weeks:	Yes
Secondary	Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD)		24 and 52 weeks post-transplantation	Yes
Secondary	Death		24 and 52 weeks post-transplantation	Yes
Secondary	Re-transplantation or Re-listed for Transplantation		24 and 52 weeks post-transplantation	No
Secondary	Incidence of Hospitalizations		24 and 52 weeks post-transplantation	Yes
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).	24 and 52 weeks post-transplantation	Yes

External Links

•   Clinical Trials in Organ Transplantation (CTOT)
•   National Institute of Allergy and Infectious Diseases (NIAID)