Use of Immune Globulin (IVIG) Plus Rituximab for Desensitization in Highly HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Cedars-Sinai Medical Center
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Stanley Jordan, MD, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier:
NCT01178216
First received: August 9, 2010
Last updated: May 6, 2014
Last verified: May 2014
  Purpose

Organ transplantation offers the only hope for a normal life for patients with end-stage renal disease on dialysis (ESRD). For patients with antibodies to human leukocyte antigens (HLA), transplantation is extremely difficult or impossible since pre-formed antibodies will cause severe rejection and loss of transplanted organs. Intravenous gamma globulin (IVIG) can reduce or eliminate these antibodies in most patients and allow for successful transplantation. This breakthrough has allowed patients previously considered not transplantable to receive life-saving transplants. However, IVIG alone does not always eradicate the anti-HLA antibodies to a degree that will allow transplantation to proceed.

In this study, the investigators propose to add an additional treatment (Rituxan), a humanized antibody directed at the CD20 antigen that is present on most B-cells (B-cells make antibodies, this Rituxan should help eliminate the source of anti-HLA by deleting the cells that make it).

Both IVIG and Rituxan are approved by the U.S. Food and Drug Administration (FDA) for numerous immunologic disorders and Non-Hodgkin's lymphoma, respectively. However, neither is yet approved by the FDA for desensitization of highly-HLA sensitized transplant patients.

Previously conducted pilot study demonstrated that IVIG + Rituxan can fill an important gap in our current therapeutic approach for management of highly sensitized patients and it may become the standard approach to manage these patients.

This study has been recently updated after observation that subjects transplanted after desensitization with IVIG alone experienced higher rates of antibody rejection and graft loss.

The primary objective of this revised protocol will be to examine the safety and efficacy of IVIG 2gm/kg (maximum dose 140g) given on day#0 & day #30 plus Rituximab 1gm given on day #15. Transplanted patients will receive additional doses of Rituximab 1gm at 3 months post-transplant if donor specific antibody (DSA)levels remain or become positive or at 6M if de novo DSA occur. All transplanted patients who remain DSA negative, will not receive additional Rituximab. All transplanted patients will have a protocol biopsy at transplant and at 12 months. All subjects will have to complete 5 visits in a pre-transplant phase of the study. Patients who are transplanted will have additional 5 post-transplant visits. The following are research-related procedures:

  1. Rituxan infusion.
  2. Kidney allograft biopsy (Intra-op and 12 months post transplant)
  3. Rituxan level, HACA levels
  4. Immunologic biomarkers (CD19+, CD38+, CD27+)

Although Dr. Jordan commonly uses both treatment regimens at Cedars-Sinai Medical Center, only the IVIG treatment is considered to be standard of care for highly HLA-sensitized patients. The investigational component of this study is the addition of the Rituxan and currently the study has been ammended to a safety and efficacy study focusing on decreasing HLA antibodies pre-transplant and minimizing DSA post transplant.


Condition Intervention Phase
End Stage Renal Disease
Biological: Rituxan
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Use of Immune Globulin Intravenous (Human), 10% (IVIG), Plus Rituximab as Agents to Reduce Donor Specific Antibodies, Improve Transplant Rates and Outcomes in Highly-HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation

Resource links provided by NLM:


Further study details as provided by Cedars-Sinai Medical Center:

Primary Outcome Measures:
  • Rates of transplantation [ Time Frame: 9 month ] [ Designated as safety issue: No ]
    This trial is designed to determine if Rituximab + IVIG can improve rates of transplantation for highly-HLA sensitized DD candidates on the UNOS waiting list over a 9M period of time after completion of treatment.


Secondary Outcome Measures:
  • Renal allograft survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • • Reduction in anti-HLA antibodies [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • • The number of acute rejection episodes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • • The number of serious infections [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • • Adverse events, toxicity assessments [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 75
Study Start Date: September 2013
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituxan
All study patients will receive Rituxan 1g on day 15 from start of desensitization and either 3M or 6M post transplant depending on the presence of DSA.
Biological: Rituxan
Rituximab (1gm) given on day# 15. Transplanted patients will receive an additional dose of Rituximab at 3M if DSA remains or 6M if denovo DSA present.
Other Name: Rituximab

Detailed Description:

This single center, Phase I/II, exploratory study has been modified to a safety/efficacy study providing all patients with IVIG and Rituximab. The trial will examine the safety and efficacy of human polyclonal IVIG 10%, when given at [2.0 gm/kgx2], + Rituximab 1gm to reduce donor-specific antibodies (DSA) to a level that is permissive for transplantation in 75 subjects (adults only ages >18 yrs) who are highly-HLA sensitized and are awaiting deceased donor kidney transplant. Once transplant offers are entertained, a donor-specific crossmatch will be performed. If acceptable crossmatches and DSA levels are seen, the patients will proceed to DD transplantation. Patients receiving transplants will receive an additional dose of IVIG at transplantation (within 10 days) and will receive additional doses of Rituximab 1g at 3M post transplant if DSA levels remain or become positive at 6M if de novo DSA occur. Patients who are desensitized and not transplanted at 9M after desensitization will have completed the study and can be treated as best judged by their physician.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. End-stage renal disease.
  2. No known contraindications for therapy with IGIV10%/Rituximab.
  3. Age 18-70 years at the time of screening.
  4. PRA> 30% demonstrated on 3 consecutive samples, UNOS wait time sufficient to allow DD offers, history of sensitizing events, positive crossmatch with the intended donor.
  5. Subject/Parent/Guardian must be able to understand and provide informed consent.

Exclusion Criteria:

  1. Lactating or pregnant females.
  2. Pediatric patients <18 years of age
  3. Women of child-bearing age who are not willing or able to practice FDA-approved forms of contraception.
  4. HIV-positive subjects.
  5. Subjects who test positive for HBV infection [positive HBVsAg, HBVcAg, or HBVeAg/DNA] or HCV infection [positive Anti-HCV (EIA) and confirmatory HCV RIBA].
  6. Subjects with active TB.
  7. Subjects with selective IgA deficiency, those who have known anti-IgA antibodies, and those with a history of anaphylaxis or severe systemic responses to any part of the clinical trial material.
  8. Subjects who have received or for whom multiple organ transplants are planned.
  9. Recent recipients of any licensed or investigational live attenuated vaccine(s) within two months of the screening visit (including but not limited to any of the following:

    • Adenovirus [Adenovirus vaccine live oral type 7]
    • Varicella [Varivax]
    • Hepatitis A [VAQTA]
    • Rotavirus [Rotashield]
    • Yellow fever [Y-F-Vax]
    • Measles and mumps [Measles and mumps virus vaccine live]
    • Measles, mumps, and rubella vaccine [M-M-R-II]
    • Sabin oral polio vaccine
    • Rabies vaccines [IMOVAX Rabies I.D., RabAvert])
  10. A significantly abnormal general serum screening lab result defined as a WBC < 3.0 X 103/ml, a Hgb < 8.0 g/dL, a platelet count < 100 X 103/ml, , an SGOT > 5X upper limit of normal, and an SGPT >5X upper limit of normal range.
  11. Individuals deemed unable to comply with the protocol.
  12. Subjects with active CMV or EBV infection as defined by CMV-specific serology (IgG or IgM) and confirmed by quantitative PCR with or without a compatible illness.
  13. Subjects with a known history of previous myocardial infarction within one year of screening.
  14. Subjects with a history of clinically significant thrombotic episodes, and subjects with active peripheral vascular disease.
  15. Use of investigational agents within 4 weeks of participation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01178216

Contacts
Contact: Jua Choi, PharmD, RD, CSNC 310-248-8186 jua.choi@cshs.org
Contact: Sabrina Louie, B.S. 310-423-1518 sabrina.louie@cshs.org

Locations
United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Principal Investigator: Stanley Jordan, MD         
Sub-Investigator: Ashley Vo, PharmD         
Sponsors and Collaborators
Stanley Jordan, MD
Genentech, Inc.
Investigators
Principal Investigator: Stanley Jordan, MD Cedars-Sinai Medical Center
  More Information

Additional Information:
Publications:
Responsible Party: Stanley Jordan, MD, Medical Director, Medical Director, Renal Transplantation & Transplant Immunotherpay, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT01178216     History of Changes
Other Study ID Numbers: Genentech-Ritux2010
Study First Received: August 9, 2010
Last Updated: May 6, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Cedars-Sinai Medical Center:
Kidney transplant
highly sensitized

Additional relevant MeSH terms:
Kidney Diseases
Kidney Failure, Chronic
Renal Insufficiency
Renal Insufficiency, Chronic
Urologic Diseases
Antibodies
Immunoglobulins
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014