Desensitization
Conditions
Keywords
belimumab, Benlysta, LymphoStat B, BLyS specific inhibitors
Brief summary
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
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.
Interventions
DRUGBelimumab
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.
Sponsors
Human Genome Sciences Inc.
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
There was no masking in this single group trial. The patients, providers and investigators were all aware that the patient were on belimumab therapy.
Intervention model description
There was only one group in this trial. All participants received belimumab.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness of Belimumab to Normalize Allo-antibody Levels in Sensitized Patients Awaiting Kidney Transplantation. | up to one year pre-transplant | 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. |
| Successful Kidney Transplantation From a Cross-match Compatible Donor (as a Result of Belimumab Therapy) | one year pre-transplant | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BLyS Levels Before and After Treatment With Belimumab | up to 8 weeks after completion of therapy | 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. |
| Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | 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. | 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. |
| Number of Participants With Treatment Related Serious Adverse Events | up to one year pre-transplant | 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. |
| Hepatitis B Vaccine Antibody Titers | up to 12 months of treatment with belimumab | 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. |
| B and T Lymphocyte Subsets | 8 weeks after the last dose of belimumab | 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. |
Countries
United States
Participant flow
Recruitment details
From April 2010 to October 2011 patients listed for renal transplant at the Hospital of the University of Pennsylvania who met study inclusion criteria and none of the exclusion criteria were approached during an outpatient clinic visit to participate in the study.
Pre-assignment details
There were no wash out, run-in or transition periods for this trial.
Participants by arm
| Arm | Count |
|---|---|
| Belimumab Belimumab is a monoclonal antibody. It is the first drug of its type in a new class of medications called BLyS-specific inhibitors. In March 2011, it was approved by the Food and Drug Administration (FDA) for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. In this study, belimumab was used in to try to decrease the amount of antibodies in the pre-kidney transplant patient's blood. This use was considered investigational (not approved by the Food and Drug Administration).
Belimumab : The subjects were given this medication as an outpatient as an intravenous infusion through the arm. The medication was given at the beginning of the study, two weeks later, and then every 4 weeks for up to one year pre-transplant. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Belimumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 41 years STANDARD_DEVIATION 26 |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 8 |
| serious Total, serious adverse events | 3 / 8 |
Outcome results
Primary
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.
Time frame: up to one year pre-transplant
Population: any patient who received at least one dose of belimumab was included in analysis population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | Effectiveness of Belimumab to Normalize Allo-antibody Levels in Sensitized Patients Awaiting Kidney Transplantation. | Patients not experiencing a decrease in antibodies | 8 Participants |
| Belimumab | Effectiveness of Belimumab to Normalize Allo-antibody Levels in Sensitized Patients Awaiting Kidney Transplantation. | Patients experiencing a decrease in antibodies | 0 Participants |
Primary
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.
Time frame: one year pre-transplant
Population: All participants enrolled who received at least one dose of belimumab were considered for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | Successful Kidney Transplantation From a Cross-match Compatible Donor (as a Result of Belimumab Therapy) | Kidney transplant as a result of belimumab therapy | 0 Participants |
| Belimumab | Successful Kidney Transplantation From a Cross-match Compatible Donor (as a Result of Belimumab Therapy) | kidney transplant unrelated to belimumab therapy | 1 Participants |
| Belimumab | Successful Kidney Transplantation From a Cross-match Compatible Donor (as a Result of Belimumab Therapy) | Kidney transplant not received during trial | 7 Participants |
Secondary
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.
Time frame: 8 weeks after the last dose of belimumab
Population: Any patient who received at least one dose of belimumab was included in the analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | B and T Lymphocyte Subsets | Decrease in T and B Cell Flow Cytometry:month 1 | 0 Participants |
| Belimumab | B and T Lymphocyte Subsets | Decease in T and B Cell Flow Cytometry:month 2 | 0 Participants |
| Belimumab | B and T Lymphocyte Subsets | Decrease in T and B Cell Flow Cytometry:month 12 | 0 Participants |
| Belimumab | B and T Lymphocyte Subsets | Decrease in T and B Cell Flow Cytometry:post 8 wks | 0 Participants |
Secondary
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.
Time frame: up to 8 weeks after completion of therapy
Population: Any patient who received at least one dose of belimumab was included in the analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | BLyS Levels Before and After Treatment With Belimumab | Unexpected change in BLyS levels at 1 month | 0 Participants |
| Belimumab | BLyS Levels Before and After Treatment With Belimumab | Unexpected change in BLyS levels at 2 month | 0 Participants |
| Belimumab | BLyS Levels Before and After Treatment With Belimumab | Unexpected change in BLyS levels at 6 mo | 0 Participants |
| Belimumab | BLyS Levels Before and After Treatment With Belimumab | Unexpected change in BLyS levels at 12 months | 0 Participants |
| Belimumab | BLyS Levels Before and After Treatment With Belimumab | Unexpected change in BLyS levels 8 wks post treat | 0 Participants |
Secondary
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.
Time frame: up to 12 months of treatment with belimumab
Population: All patients who received at least one dose of belimumab were included in the analysis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | Hepatitis B Vaccine Antibody Titers | Patients who maintained Hepatitis B titer | 7 Participants |
| Belimumab | Hepatitis B Vaccine Antibody Titers | Patients who did not maintain Hepatitis B titer | 0 Participants |
Secondary
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.
Time frame: up to one year pre-transplant
Population: Any patient who received at least one dose of belimumab was included in the analysis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | Number of Participants With Treatment Related Serious Adverse Events | Hives/infusion reaction related to belimumab | 1 Participants |
| Belimumab | Number of Participants With Treatment Related Serious Adverse Events | No SAEs possibly/definitely related to belimumab | 7 Participants |
Secondary
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.
Time frame: 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.
Population: any patient who received at least one dose of belimumab was included in the analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belimumab | Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | Pre Dose Belimumab Serum Dilution at 400-Day 0 | 8 Participants |
| Belimumab | Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | Pre Dose Belimumab Serum Dilution at 8000-Day 56 | 7 Participants |
| Belimumab | Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | Pre Dose Belimumab Dilution 8000 at Day 364 | 2 Participants |
| Belimumab | Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | Post Dose Belimumab Dilution at 8000 at Day 14 | 7 Participants |
| Belimumab | Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | Post Dose Belimumab Dilution at 8000 at Day 168 | 6 Participants |
| Belimumab | Pharmacokinetics of Belimumab Measured as Number of Participants With Specific Dilution Factors at Each Time Point. | Belimumab Dilution 8000 at 8 weeks After Belimumab | 2 Participants |