Desensitization With Belimumab in Sensitized Patients Awaiting Kidney Transplant

Study Overview
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Brief Summary
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If subjects are listed for kidney transplant and are considered sensitized, this means they have a high amount of antibodies in their blood that could react to a kidney transplant offered for them. Antibodies are protein substances made by the body that fight anything that the body considers as a threat to it, such as infection or a kidney transplant. Sensitization may be due to prior transplants, pregnancy, or blood transfusions. Being sensitized can increase the subject's kidney transplant waiting time as it is more difficult to find a suitable kidney transplant for them that their antibodies will not react to. The purpose of this research study is to see if giving the investigational drug belimumab up to one year pre-transplant can de-sensitize the subjects, or decrease the amount of antibodies in their blood. This may help make the subjects eligible to receive a kidney transplant more quickly. If after receiving belimumab, the subjects are compatible with a donor kidney offered and are medically suitable for transplant at that time, a kidney transplant will be performed.

Detailed Description
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Approximately one third of patients awaiting kidney transplant at our transplant center have significant levels of antibodies in their blood leading to a longer wait time for a kidney transplant and death. Antibodies in the blood may be due to prior transplants, pregnancy, or blood transfusions. These antibodies sensitize a patient and make it more difficult for the patient to get a compatible kidney transplant. The measure of these antibodies is called panel reactive antibodies (PRA) and can range from 0-100%, with 100% being most sensitized. The waiting time for patients with a PRA in the range of 20%-79% is over 5 years as compared to patients with low PRA (0%-19%) which is 3-4 years. Patients with a PRA greater than 80% are likely to be granted extra points to increase the chances of transplantation. Antibodies in these patients may be due to prior transplants, pregnancy, or blood transfusions. To date, no trials with belimumab have been performed in patients with pre-existing antibodies awaiting kidney transplantation. This study is undertaken to assess the effectiveness and safety of using belimumab to normalize antibody levels in sensitized patients awaiting kidney transplantation. It is hoped that decreasing these antibodies will decrease the waiting time on the kidney transplant list, and allow the patient to become compatible with a donor kidney for transplant.

Official Title
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One Year Exploratory Study to Evaluate the Efficacy and Safety of Belimumab for Normalization of Alloantibody Levels in Sensitized Patients Awaiting Kidney Transplantation

Conditions
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Desensitization

Intervention / Treatment
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* Drug: Belimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 -75 years. Patients denied a kidney transplant because of a prior positive crossmatch Patients awaiting a first or second kidney transplant from a living or deceased donor Patients who have given written informed consent to participate in all aspects of the study. Patients with no potential living donors should have accumulated at least 12 months waiting time in our organ procurement organization And one of the following criteria: Pre-sensitized patients defined by Luminex antibody assays and whose panel reactive antibody (PRA) is 20% or greater Patients with a PRA of less than 20% but who have HLA antibody specificities to HLA-Cw, DP or allele-specific antigens Exclusion Criteria: Patients with known hypersensitivity to belimumab or who have received biologics, within the last 90 days Patients receiving corticosteroids, intravenous immunoglobulin, cyclophosphamide, mycophenolate mofetil, or azathioprine from 90 days prior to study entry until day of transplant. Patients with a history of anaphylaxis to parenteral administration of contrast agents, foreign proteins, or monoclonal antibodies. Patients with multi-organ transplant Patients who have received any investigational immunosuppressive drug within 1 month of inclusion into this study or if use of such a product is anticipated. Patients who have received any live vaccine within 30 days of study entry. Female patients who are pregnant, lactating. Female patients of child bearing potential and not willing to practice an approved method of birth control for 1 month prior to the start of the study agent and 8 weeks after the last dose of study agent. Male patients who are not agreeable to using effective contraception throughout the study and for 3 months after the last dose of study agent. Patients with a known malignancy or history of malignancy other than excised basal or squamous cell carcinoma of the skin. Patients who are positive for Hepatitis B infection, Hepatitis C infection or Human Immunodeficiency Virus (HIV)-positive patients. Patients with evidence of severe liver disease, including abnormal liver profile tests > 3 times upper limit of normal at screening. Patients with current severe infection. Patients with any surgical or medical condition, which in the opinion of the investigator precludes enrollment in this trial Patients who live far from the transplant center and are unable to comply with all study visits.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: There was only one group in this trial. All participants received belimumab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belimumab<br>Belimumab will be administered intravenously at a dose of 10mg/kg on days 0, 14, 28 and every 28 days for up to 52 weeks to normalize alloantibody levels in sensitized patients awaiting kidney transplantation. Subjects who are not able to undergo transplantation before the end of the treatment period will have final follow-up evaluation 8 weeks after the last dose of belimumab is administered. | Drug: Belimumab<br>* Belimumab is a fully human monoclonal antibody that recognizes and inhibits BLyS ®. BLyS ® is a B-lymphocyte stimulator protein which plays a role in the development of B lymphocyte cells into plasma B cells, which then produce antibodies that can sensitize a potential transplant recipient. At the time of this trial, belimumab was not yet FDA approved and was being studied in clinical trials for the treatment of systemic lupus erythematosus. Until this trial, it had not yet been used in the transplant setting.<br>* Other names: also previously known as LymphoStat-B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness of Belimumab to Normalize Allo-antibody Levels in Sensitized Patients Awaiting Kidney Transplantation. | Before transplant it is necessary to measure antibodies that the recipient might have and compare them to the living or decease donor's immune make-up. Recipients with many antibodies or a specific antibody in a high concentration may have a more difficult time finding a compatible donor, and being transplanted. These recipients are referred to as sensitized patients. It is important that the sensitized recipient and the donor be compatible to prevent rejection after transplant. We measured antibodies levels in sensitized patients waiting for kidney transplant, to see if belimumab would decrease these antibody levels. | up to one year pre-transplant | 
| Successful Kidney Transplantation From a Cross-match Compatible Donor (as a Result of Belimumab Therapy) | In order for a sensitized recipient ( a recipient with antibodies) to be transplanted, the cross match with the donor has to be compatible. We wanted to study if belimumab reduced antibodies in sensitized patients and led those patients to subsequently become cross-match compatible with a donor and allow for successful transplant. | one year pre-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | We wanted to look at belimumab pharmacokinetics in sensitized patients awaiting kidney transplant. These are reported as number of participants with specific dilution factors at each studied time-point. Blood for these tests could be drawn pre dose as well as 0-4 hours after the dose was given. Belimumab dilutions factors were measured pre dose at timepoints 0 (first day of belimumab), days 56 and 364. Belimumab dilution factors were measured after the dose on days 14, and 168. Belimumab dilution factors were also measured at 8 weeks after completion of belimumab therapy and pre dose at any unscheduled visits if needed. | Belimumab serum drug dilution factors were measured in patients at at timepoints 0 (first day of belimumab), day 14, day 56, day 168, 364, at any unscheduled visits, and at 8 weeks post completion of belimumab therapy. | 
| B and T Lymphocyte Subsets | B and T Lymphocyte subsets were measured through flow cytometry pre-treatment and at months 1,2,12 and at 8 weeks after the last belimumab dose. We looked for clinically significant changes (as determined by Principal Investigator) in these subsets at each time-point. | 8 weeks after the last dose of belimumab | 
| BLyS Levels Before and After Treatment With Belimumab | We assessed for unexpected changes in bound and unbound BLyS levels before and after treatment with belimumab. These were measured from before treatment and at months 1,2,6,10 and 12 months after belimumab treatment and again at 8 weeks after belimumab treatment. | up to 8 weeks after completion of therapy | 
| Hepatitis B Vaccine Antibody Titers | We investigated if belimumab treatment would decrease Hepatitis B vaccine titers by 12 months after treatment with belimumab. All patients received Hepatitis B vaccine before beginning treatment with belimumab. | up to 12 months of treatment with belimumab | 
| Number of Participants With Treatment Related Serious Adverse Events | To assess the safety of belimumab in sensitized patients awaiting kidney transplant we evaluated the number of participants with serious adverse events possibly or definitely related to belimumab. | up to one year pre-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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belimumab, Benlysta, LymphoStat B, BLyS specific inhibitors