Rituximab + Immune Globulin Intravenous (IVIG) for Desensitization
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Purpose
Organ transplantation offers the only hope for a normal life for patients with end-stage renal disease on dialysis (ESRD). For the highly-sensitized patient, 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 on 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 preset 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 to these patients and it may become the standard approach to highly-sensitized patients.
This study aims to compare the effect of IVIG 10% (2gm/kg) given on days #0 & 30 + Rituximab (1gm) given day# 15 vs IVIG (2gm/kg) given on days #0 & 30 + placebo given on day # 15.
Subjects who have end-stage renal disease (ESRD) with high level of pre-formed anti-HLA antibodies will be randomized to one of the following treatment groups:
- Group 1 - patients randomized to this group will receive IVIG and Rituxan
- Group 2 - patients randomized to this group will receive IVIG and placebo.
This trial is designed to determine if Rituximab + IVIG is superior to IVIG treatment alone in improving rates of transplantation for highly-HLA sensitized deceased donor (DD) candidates on the UNOS waiting list.
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.
| Condition | Intervention | Phase |
|---|---|---|
|
End Stage Renal Disease |
Biological: Rituxan |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment |
| Official Title: | Comparison of Immune Globulin Intravenous (Human), 10% (IVIG), Plus Rituximab vs. IVIG 10% + Placebo as Agents to Reduce Donor Specific Antibodies, Improve Transplant Rates and Outcomes in Highly-HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation |
- Rates of transplantation [ Time Frame: 6 month ] [ Designated as safety issue: No ]This trial is designed to determine if Rituximab + IVIG is superior to IVIG treatment alone in improving rates of transplantation for highly-HLA sensitized DD candidates on the UNOS waiting list over a 6M period of time after completion of treatment.
- Renal allograft survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- • Reduction in anti-HLA antibodies [ Time Frame: 6 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: | 90 |
| Study Start Date: | December 2010 |
| Estimated Study Completion Date: | May 2014 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Active Comparator: Rituxan |
Biological: Rituxan
Rituximab (1gm) given on day# 14. Transplanted patients will receive an additional dose of Rituximab at months 6.
Other Name: Rituximab
|
| Placebo Comparator: placebo |
Biological: Rituxan
Rituximab (1gm) given on day# 14. Transplanted patients will receive an additional dose of Rituximab at months 6.
Other Name: Rituximab
|
Detailed Description:
This single center, Phase I/II, exploratory study will use a blinded placebo controlled design. The trial will examine the safety and efficacy of human polyclonal IGIV 10%, when given at [2.0 gm/kgx2], + Rituximab 1gm to reduce donor-specific antibodies (DSA) to a level that is permissive for deceased donor (DD) transplantation in 45 subjects (adults only ages >18 yrs) who are highly-HLA sensitized and are awaiting DD kidney transplant. This will be compared to 45 HS patients who are treated with IVIG 10% [2.0 gm/kgx2] + placebo (normal saline). Once transplant offers are entertained, a donor-specific crossmatch will be performed to detect anti-HLA antibodies which are associated with acute rejection or graft loss. (These anti-HLA antibodies may result naturally or from some previous pregnancy, transfusions, or prior transplants.) If acceptable crossmatches and DSA levels are seen, the patients will proceed to DD transplantation. Patients receiving transplants from both groups will receive an additional dose of IVIG at transplantation (within 10 days) and will receive additional doses of Rituximab 1g or placebo (normal saline) at 6M post-transplant (Fig 5 & 6). Patients who are desensitized and not transplanted within 6M 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 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- End-stage renal disease.
- No known contraindications for therapy with IGIV10%/Rituximab.
- Age 18-65 years at the time of screening.
- 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.
- Subject/Parent/Guardian must be able to understand and provide informed consent.
Exclusion Criteria:
- Lactating or pregnant females.
- Pediatric patients <18 years of age
- Women of child-bearing age who are not willing or able to practice FDA-approved forms of contraception.
- HIV-positive subjects.
- Subjects who test positive for HBV infection [positive HBVsAg, HBVcAg, or HBVeAg/DNA] or HCV infection [positive Anti-HCV (EIA) and confirmatory HCV RIBA].
- Subjects with active TB.
- 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.
- Subjects who have received or for whom multiple organ transplants are planned.
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])
- 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.
- Individuals deemed unable to comply with the protocol.
- 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.
- Subjects with a known history of previous myocardial infarction within one year of screening.
- Subjects with a history of clinically significant thrombotic episodes, and subjects with active peripheral vascular disease.
- Use of investigational agents within 4 weeks of participation.
Contacts and Locations| United States, California | |
| Cedars-Sinai Medical Center | |
| Los Angeles, California, United States, 90048 | |
| 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: | September 6, 2012 |
| 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, Chronic Renal Insufficiency Antibodies Immunoglobulins Immunoglobulins, Intravenous Rho(D) Immune Globulin |
Rituximab Urologic Diseases Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antirheumatic Agents Therapeutic Uses Antineoplastic Agents |
ClinicalTrials.gov processed this record on May 19, 2013