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

NCT01769443 | Terminated Phase 2 Results DMC

• 2 other identifiers: DAIT CTOT-13U01AI063594
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 14

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.

Conditions

Primary Heart Transplant; Heart Transplantation; Heart Transplant

Keywords

desensitization therapy; bortezomib (VELCADE®); plasmapheresis

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (18)

• Time From Wait Listing to Heart Transplantation

  At transplant, or 1 year post-randomization, whichever occurs first

• 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

Study Arms (2)

No Desensitization Therapy

NO INTERVENTION

Subject(s) randomized to no desensitization therapy pre-transplant.

Desensitization Therapy

EXPERIMENTAL

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.

Drug: bortezomib; Procedure: plasmapheresis

Interventions

bortezomib DRUG

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.

Also known as: VELCADE®

Desensitization Therapy

plasmapheresis PROCEDURE

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.

Also known as: apheresis (plasma)

Desensitization Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (14)

Cedars Sinai Heart Institute

Beverly Hills, California, 90211, United States

Location

University of California at San Francisco

San Francisco, California, 94143, United States

Location

Yale New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Minneapolis Heart Institute

Minneapolis, Minnesota, 55407, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Drexel University College of Medicine

Philadelphia, Pennsylvania, 19102, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

The Methodist Hospital

Houston, Texas, 77030, United States

Location

Intermountain Medical Center

Murray, Utah, 84157, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related 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. doi: 10.1161/01.cir.100.suppl_2.ii-229.

  PMID: 10567309 BACKGROUND

• 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. doi: 10.1097/01.TP.0000080685.31697.FC.

  PMID: 12973100 BACKGROUND

• 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. doi: 10.1111/j.1399-0012.2006.00509.x.

  PMID: 16842525 BACKGROUND

• 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.

  PMID: 18442726 BACKGROUND

Related Links

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

MeSH Terms

Interventions

Bortezomib; Plasmapheresis; Blood Component Removal

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative

Limitations and Caveats

Study was terminated by the study sponsor, with agreement from the investigators. Reason: very slow rate of accrual and inability to meet the accrual goal within the funding period. (N=2 enrolled. Aim was 80 participants).

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Jon A Kobashigawa, MD

  Cedars-Sinai Heart Institute

  STUDY CHAIR

• Peter S. Heeger, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2013
• First Posted: January 16, 2013
• Study Start: June 1, 2013
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: November 11, 2015
• Results First Posted: November 11, 2015

Record last verified: 2015-10

Locations

US (14)