Belatacept in Kidney Transplantation of Moderately Sensitized Patients

NCT02130817 | Withdrawn Phase 4 DMC

• 2 other identifiers: Should be 2013-0672IM103-327
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

End Stage Renal Disease; Antibody Mediated Rejection

Keywords

Renal Transplant; Kidney Transplant; Mean flourescent Intensity; Delayed Graft Function; Antagonist of Thymocyte Cell Activation

Outcome Measures

Primary Outcomes (1)

• Acute rejection

  Acute rejection rates are based on assessment of standard of care biopsy (protocol and indication) and standard Banff criteria.

  one year

Secondary Outcomes (6)

• Patient and Graft Survival

  One year

• Incidence of infections

  One year

• Incidence of de novo donor specific antibody (DSA)

  One year

• Incidence of new onset diabetes

  One year

• Increase in estimated Glomerular Filtration Rate (eGFR)

  One year

Study Arms (1)

Belatacept

EXPERIMENTAL

Belatacept (nujolix): Tacrolimus withdrawal Standard of care(SOC) treatment: Plasmapheresis/Intravenous Immunoglobulin G (IVIG) therapy Thymoglobulin will be administered to a total cumulative dose of 4.5-6 mg/kg starting in the operating room. Maintenance immunosuppression: Myfortic: Patients will receive 720mg bid of Myfortic throughout the study, starting day 1 after surgery. Steroids: Patients will receive Dexamethasone IV on the day of surgery (Day 0) with tapered doses through Day 4 followed by prednisone tapered to 10mg/d by day 30.

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

Interventions

Belatacept DRUG

Belatacept will be added to the standard of care regimen and will be given at days 0,5, weeks 2, 4, 8 and 12 (10 mg/kg) and every 4 weeks (5 mg/kg) for one year.

Also known as: Nujolix

Belatacept

Tacrolimus withdrawal DRUG

Tacrolimus dosing will begin on Days 1 through 5 post transplant at up to 2 mg BID to achieve target trough levels of 9-11 ng/ml. The dose will be tapered through the end of week 2 to achieve a trough level of 4 ng/ml which will be maintained for six weeks. Tacrolimus will be withdrawn at the end of eight weeks post transplant.

Belatacept

Plasmapheresis/Intravenous Immunoglobulin G PROCEDURE

Enrolled patients will start with standard of practice treatment including plasmapheresis and IVIG therapy twice after transplant, on days 2 and 4 and potentially once before transplant. Plasmapheresis and albumin exchange for one volume of blood will be performed in the infusion center at the University of Wisconsin Hospital and Clinics (UWHC). Each pheresis session will be completed by IVIG infusion. While plasmapheresis will help with the removal of circulating Donor Specific Antibodies (DSA), IVIG therapy will provide immunomodulatory characteristics that include sterilizing immunity from infections, inhibiting and scavenging activated complement fragments, modifying cell-mediated immune responses, inducing regulatory T cells and importantly, inhibiting deleterious antibody production.

Belatacept

Thymoglobulin (ATG) DRUG

Thymoglobulin (ATG) Induction. Thymoglobulin will be administered to a total cumulative dose of 4.5-6 mg/kg via a peripheral or central vein, starting in the operating room.

Also known as: Anti-thymocyte globulin

Belatacept

Myfortic DRUG

Patients will receive 720mg bid of Myfortic throughout the study, starting day 1 after surgery.

Belatacept

Steroids DRUG

Patients will receive Dexamethasone IV on the day of surgery (Day 0) with tapered doses through Day 4 followed by prednisone tapered to 10mg/d by day 30.,

Also known as: Dexamethasone, Prednisone

Belatacept

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

University of Wiscsonsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

Related Publications (10)

• 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.

  PMID: 19461494 BACKGROUND

• Jordan SC, Pescovitz MD. Presensitization: the problem and its management. Clin J Am Soc Nephrol. 2006 May;1(3):421-32. doi: 10.2215/CJN.01651105. Epub 2006 Apr 12.

  PMID: 17699241 BACKGROUND

• 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. doi: 10.1111/j.1600-6143.2005.01178.x.

  PMID: 16426319 BACKGROUND

• 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.

  PMID: 18635429 BACKGROUND

• 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. doi: 10.1111/j.1399-3046.2004.00214.x.

  PMID: 15598320 BACKGROUND

• 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.

  PMID: 18622284 BACKGROUND

• 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.

  PMID: 19155983 BACKGROUND

• 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.

  PMID: 19584672 BACKGROUND

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

  BACKGROUND

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

  BACKGROUND

MeSH Terms

Conditions

Kidney Failure, Chronic; Delayed Graft Function

Interventions

Abatacept; Plasmapheresis; thymoglobulin; Antilymphocyte Serum; Mycophenolic Acid; Steroids; Dexamethasone; Prednisone

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Blood Component Removal; Therapeutics; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative; Immune Sera; Immunoproteins; Biological Products; Complex Mixtures; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids, Fluorinated; Pregnadienediols

Study Officials

• Arjang Djamali, M.D.

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2014
• First Posted: May 5, 2014
• Study Start: September 24, 2014
• Primary Completion: October 9, 2015
• Study Completion: October 9, 2015
• Last Updated: December 17, 2018

Record last verified: 2018-12

Locations

US (1)