Belatacept in Kidney Transplantation of Moderately Sensitized Patients

Condition(s) targeted: End Stage Renal Disease; Antibody Mediated Rejection

Intervention: Belatacept (Drug); Tacrolimus withdrawal (Drug); Plasmapheresis/Intravenous Immunoglobulin G (Procedure); Thymoglobulin (ATG) (Drug); Myfortic (Drug); Steroids (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: University of Wisconsin, Madison

Official(s) and/or principal investigator(s):
Arjang Djamali, M.D., Principal Investigator, Affiliation: University of Wisconsin, Madison

Overall contact:
Arjang Djamali, M.D., Phone: 608-262-9306, Email: axd@medicine.wisc.edu

The purpose of this study is to evaluate the safety and effectiveness of an immunosuppressive medication, Belatacept, as a replacement for a calcineurin inhibitor, in combination with a standard of care regimen of immunosuppressive medications and plasma exchange (plasmapheresis and immunoglobulin treatment) for kidney transplant patients who are moderately sensitized against their deceased donor and at-risk for delayed graft function. The hypothesis is that moderately sensitized patients who receive Belatacept treatment with the standard of care regimen will lead to lower acute rejection rates than historical controls based on assessment of standard of care biopsies and standard Banff criteria.

Official title: Belatacept for the Management of Moderately Sensitized Patients at Risk for Delayed Graft Function (DGF)

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Acute rejection

Secondary outcome:

Patient and Graft Survival

Incidence of infections

Incidence of de novo donor specific antibody (DSA)

Incidence of new onset diabetes

Increase in estimated Glomerular Filtration Rate (eGFR)

Incidence of malignancies

Detailed description: This exploratory single-center, open-label safety and efficacy study will enroll 20 adult kidney transplants candidates, moderately sensitized against their deceased donor and at-risk for delayed graft function (DGF), to receive Belatacept (days 0,5, weeks 2,4,8 and 12 (10 mg/kg), and every 4 weeks thereafter (5 mg/kg)), plasma exchange (once before and twice after transplant) and Intravenous Immunoglobulin (IVIG) (100 mg/kg after each plasma exchange), along with Thymoglobulin (ATG) induction and Dexamethasone tapered dosing starting on the day of transplant at 100mg IV, tapered through Day 4, followed by prednisone at 30 mg on Day 5 with tapered dosing to prednisone 10 mg/d by one month, with a total observation period of 1 year. Patients will be tapered off tacrolimus by week 8 and will remain on mycophenolic acid and prednisone for the total length of the study. Subjects will be followed until 1 year post transplant.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Male or female subjects 18-70 years of age

- Patient who is receiving an expanded criteria donor (ECD) or deceased cardiac donor

(DCD) kidney

- Have immunodominant donor specific antibodies (DSA) 1,000 - 4,000 mean fluorescent

intensity (MFI) by single bead Luminex bioassay

- Subjects must be capable of understanding the investigational nature and risks of the

study and must sign a statement of informed consent

- Female patients of child bearing potential must have a negative urine or serum

pregnancy test within the past 48 hours prior to study inclusion and be willing to use contraceptives for the duration of the study and for 8 weeks after the last dose of study drug Women of Child-Bearing Potential (WOCBP) includes

- Women who have experienced menarche and who have not undergone successful surgical

sterilization or who are not post-menopausal

- Women using oral contraceptives, other hormonal contraceptives, or mechanical

products such as intrauterine devices or barrier methods

- Women who are practicing abstinence

- Women who have a partner who is sterile (eg, due to vasectomy).

- Women must not be breast-feeding

- Male subjects must agree to use an acceptable method for contraception for the

duration of the study

- Patient must have known positive Epstein-Barr virus (EBV) serostatus

Exclusion Criteria:

- Patient has previously received an organ transplant other than a kidney.

- Patient is receiving an human leukocyte antigen (HLA) identical living donor

transplant

- Patient who is a recipient of a multiple organ transplant

- Patient with a positive T or B cell crossmatch

- Patient with a donor specific antibody (DSA) as deemed by the local PI to be

associated with significant risk of rejection

- Patient has received an ABO incompatible donor kidney

- Recipients will be receiving a dual or en bloc kidney transplant

- Donor anticipated cold ischemia is > 30hours

- Recipient or donor is known to be seropositive for hepatitis C virus (HCV) or B virus

(HBV) except for hepatitis B surface antibody positive. HCV seropositive patients with a negative HCV viral load testing may be included.

- Recipient or donor is known to be seropositive for human immunodeficiency virus (HIV)

- Seronegative or unknown EBV serostatus

- Patient has uncontrolled concomitant infection or any other unstable medical

condition that could interfere with the study objectives

- Patients with tuberculosis who have not been treated for latent infection.

- Patients at high risk for polyoma virus-associated nephropathy, which is mostly due

to BK virus infection

- Patients at high risk for polyoma virus-associated nephropathy, which is mostly due

to BK virus infection

- Patients with thrombocytopenia (PLT <75,000/mm3), and/or leucopoenia (WBC <

2,000/mm3), or anemia (hemoglobin < 6 g/dL) prior to study inclusion.

- Patient is taking or has been taking an investigational drug in the 30 days prior to

transplant

- Patient who has undergone desensitization therapy within 6 months prior to transplant

- Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate

mofetil, alemtuzumab, rabbit anti-thymocyte globulin, or glucocorticoids

- Patient is receiving chronic steroid therapy at the time of transplant

- Patients with a history of cancer (other than non-melanoma skin cell cancers cured by

local resection) within the last 5 years

- Patients with > Grade 2 peripheral neuropathy within 14 days before enrollment

- Myocardial infarction within 6 months prior to enrollment or New York Heart

Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiography evidence of acute ischemia or active conduction system abnormalities.

- Female subject is pregnant or breast-feeding

- Serious medical or psychiatric illness likely to interfere with participation in this

clinical study. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness

- Prisoners or subjects who are involuntarily incarcerated

Arjang Djamali, M.D., Phone: 608-262-9306, Email: axd@medicine.wisc.edu

University of Wiscsonsin Hospital and Clinics, Madison, Wisconsin 53792, United States; Recruiting
Arjang Djamali, M.D., Phone: 608-262-9306, Email: axd@medicine.wisc.edu
Lynn Jacobson, M.S., Phone: 608-263-3369, Email: lmj@medicine.wisc.edu
Arjang Djamali, M.D., Principal Investigator

Related publications:

Trivedi HL, Terasaki PI, Feroz A, Everly MJ, Vanikar AV, Shankar V, Trivedi VB, Kaneku H, Idica AK, Modi PR, Khemchandani SI, Dave SD. Abrogation of anti-HLA antibodies via proteasome inhibition. Transplantation. 2009 May 27;87(10):1555-61. doi: 10.1097/TP.0b013e3181a4b91b.

Jordan SC, Pescovitz MD. Presensitization: the problem and its management. Clin J Am Soc Nephrol. 2006 May;1(3):421-32. Epub 2006 Apr 12. Review.

Stegall MD, Gloor J, Winters JL, Moore SB, Degoey S. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant. 2006 Feb;6(2):346-51.

Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, Peng A, Villicana R, Jordan SC. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008 Jul 17;359(3):242-51. doi: 10.1056/NEJMoa0707894.

Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: a single center's perspective. Pediatr Transplant. 2004 Dec;8(6):535-42.

Magee CC, Felgueiras J, Tinckam K, Malek S, Mah H, Tullius S. Renal transplantation in patients with positive lymphocytotoxicity crossmatches: one center's experience. Transplantation. 2008 Jul 15;86(1):96-103. doi: 10.1097/TP.0b013e318176ae2c.

Thielke JJ, West-Thielke PM, Herren HL, Bareato U, Ommert T, Vidanovic V, Campbell-Lee SA, Tzvetanov IG, Sankary HN, Kaplan B, Benedetti E, Oberholzer J. Living donor kidney transplantation across positive crossmatch: the University of Illinois at Chicago experience. Transplantation. 2009 Jan 27;87(2):268-73. doi: 10.1097/TP.0b013e3181919a16.

Jordan SC, Toyoda M, Vo AA. Intravenous immunoglobulin a natural regulator of immunity and inflammation. Transplantation. 2009 Jul 15;88(1):1-6. doi: 10.1097/TP.0b013e3181a9e89a. Review.

Investigator Brochure. Belatacept (BMS-2224818), Version 13. Bristol-Myers Squibb Research and Development Department. 15 December 2010.

U.S. Prescribing information for Nulojix® (belatacept), Revised 06/2011. Bristol-Myers Squibb.

Starting date: May 2014
Last updated: July 2, 2014