A Study of Belimumab in the Prevention of Kidney Transplant Rejection

BEL114424: A Phase 2 Pilot, Multicentered, Randomised, Double Blind, Placebo-Controlled Study to Evaluate the Potential for Efficacy and the Safety of Belimumab Plus Standard of Care Versus Placebo Plus Standard of Care in the Prevention of Allograft Rejection in Adult Subjects After Renal Transplantation

Kidney transplantation is the best treatment for many patients with kidney failure. Sometimes a transplanted kidney is rejected by the patient's immune system. Many types of immune system cells, including B cells, are active in rejection. B cells produce antibodies against anything the body sees as non-self, like germs or a transplanted kidney. Most medicines that help prevent transplant rejection affect cells other than B cells. Belimumab is a medication used to treat a disease called lupus. Belimumab slows development of antibody-producing B cells. This study will test whether belimumab works on parts of the immune system that cause rejection. Twenty to thirty adults getting a kidney transplant will be in this study. Like flipping a coin, a computer will randomly assign half to be given belimumab and half to be given placebo (a fake medicine). Patients and doctors will not know which medicine was assigned until the study is over. A total of 7 doses of study medicine will be given through a vein. One dose will be given during transplant surgery, and the other 6 will be given 2, 4, 8, 12, 16 and 20 weeks after transplant surgery. Usual transplant medicines will also be given. After all of the doses have been given, patients will be watched and tested at 24, 36, and 52 weeks after the transplant surgery. Blood samples will be tested to see what study medicines do to the immune system in transplant patients. If patients get a kidney biopsy, the samples will be tested to see if belimumab had any effect. Patients will be asked many questions to see if they are having any side effects. The study will be done at Addenbrooke's Hospital in Cambridge and Guys &St Thomas Hospital in London, United Kingdom. A pharmaceutical company, GlaxoSmithKline, is funding the study.

Inclusion Criteria:

• Eligible for kidney transplantation: Considered eligible for transplantation after undergoing multidisciplinary evaluation at the institution at which the transplantation will be performed
• Donor characteristics: Receiving a deceased donor kidney or a living donor kidney allograft
• Age & Gender: Male or female between 18 and 75 years of age, inclusive, at the time of signing the informed consent
• Female Subjects: Not pregnant or nursing and at least one of the following conditions apply: a. Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea. In the absence of confirmatory laboratory assessments [(a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 million international units per milliliter (MIU/mL) and estradiol < 40 picogram per milliliter (pg/mL) (<147 picomole per liter [pmol/L])] in questionable cases, female subjects will be required to use one of the contraception methods as described by the investigator or designee, until confirmatory results become available; b. Questionable post-menopausal status and agrees to use one of the contraception methods as described by the investigator or designee, from Day 0 until 16 weeks after the last dose of investigational product or until postmenopausal status is confirmed with a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol status who are using hormone replacement therapy (HRT) will be required to use one of the contraception methods as described by the investigator or designee, until post-menopausal status is confirmed. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method; c. Child-bearing potential and agrees to use one of the contraception methods as described by the investigator or designee, from Day 0 until 16 weeks after the last dose of investigational product.
• Liver function (most recent values available before transplantation): alanine aminotransferase (ALT) < 2x upper limit of normal (ULN); bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Immunosuppressants: at the time of transplantation, planned to receive a combination of immunosuppressants including basiliximab, mycophenolate mofetil, tacrolimus, prednisolone

Exclusion Criteria:

• Donor characteristics: receiving a kidney allograft from a donor with any of the following characteristics: a) cold ischemic time exceeding 36 hours; b) age < 5 years old; c) for donors after brain death (DBD), age >70 years old; d) for donors after cardiac death (DCD) age >70 years old; e) ABO blood type incompatible against the recipient; f) 0 0 0 HLA-A -B -DR mismatch against the recipient by National Health Service Blood and Transplant (NHSBT criteria; g) T- and/or B-cell positive crossmatch by complement dependent cytotoxicity or flow cytometry against the recipient. Note :- (In some situations it may be that a pre-existing T- and/or B-cell positive crossmatch by complement dependent cytotoxicity or flow cytometry against the recipient will only be fully revealed immediately after the transplant; in such situations they will be recorded as having met exclusion criteria and withdraw from further involvement in the study; h) serology positive for hepatitis B (except hepatitis B surface antibody and prior vaccination), hepatitis C or human immunodeficiency virus (HIV)
• Transplant other than kidney: has previously received a hematopoietic stem cell/marrow transplant or an organ transplant other than a kidney (with the exception of corneal transplantation)
• Planned immunosuppressant regimen: are being considered for steroid-free or alemtuzumab induction
• Prior therapy at any time: has ever received any of the following: a) B-cell targeted therapy (e.g., rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI fragment, crystallizable (Fc), or belimumab)
• 364 Day prior therapy: has received any of the following within 364 days before Day 0: a) Cyclophosphamide; b) Abatacept; c) A biologic investigational agent other than B-cell targeted therapy [e.g., abetimus sodium, anti CD40L antibody (e.g., BG9588/ IDEC 131; investigational agent applies to any drug not approved for sale in the country in which it is being used]
• 90 Day prior therapy: has received any of the following within 90 days before Day 0: a) Anti- Tumor necrosis factor (TNF) or anti-Interleukin (IL)-6 therapy (e.g., adalimumab, etanercept, infliximab, tocilizumab); b) Interleukin-1 receptor antagonists (e.g., anakinra); c) Intravenous immunoglobulin (IVIG); d) Plasmapheresis, leukapheresis
• 60 Day prior therapy: has received any of the following within 60 days before Day 0: a) A non-biologic investigational agent (investigational agent applies to any drug not approved for sale in the country in which it is being used); b) Any new immunosuppressive/immunomodulatory agent; tacrolimus, Mycophenolate mofetil (MMF), and corticosteroids are permitted. Inhaled steroids and new topical immunosuppressive agents (e.g., eye drops, topical creams) are also allowed.
• 30 Day prior therapy: has received any of the following within 30 days before Day 0: a) A live vaccine; b) An increase in dose of an immunosuppressive/immunomodulatory agent (decreases in dose or discontinuations are permitted). Increases in doses of tacrolimus, MMF, and corticosteroids are permitted.
• Malignancy: has a history of malignancy in the past 5 years except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
• Acute or chronic infection: has required management of acute or chronic infections (excludes prophylaxis of infections), as follows: a) Currently receiving any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria), which, in the opinion of the investigator, could put the subject at undue risk; b) Hospitalized for treatment of infection within 30 days before Day 0, which, in the opinion of the investigator, could put the subject at undue risk ; c) Treated for an infection with parenteral (intravenous or intramuscular)] antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 30 days before Day 0, which, in the opinion of the investigator, could put the subject at undue risk
• Other disease/conditions: has any of the following: a) clinical evidence of significant unstable or uncontrolled acute or chronic diseases (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, neurological, malignancy or infectious diseases) which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk; b) a surgical procedure planned in the 6 months after Day 0, other than kidney transplantation or related procedure; c) a known history of any other medical disease (e.g., cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access) that, in the opinion of the investigator, makes the subject unsuitable for the study
• Hepatitis: known to have serologic evidence of hepatitis B infection based on the results of testing for hepatitis B surface antigen (HBsAg), or antibodies against hepatitis B core antigen (HBc) and/or hepatitis B surface antigen (HBs) as follows: a) Patients positive for HBsAg are excluded; ) Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody and with no history of hepatitis B vaccination are excluded; c) Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are excluded; d) Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are excluded; e) Or has known serologic evidence of hepatitis C infection based on the results of testing for hepatitis C antibody and hepatitis C recombinant immunoblot assay (RIBA) as follows: Patients with a positive test for Hepatitis C antibody confirmed on the same sample with a Hepatitis C RIBA immunoblot assay. Patients who are positive for Hepatitis C antibody, and who are negative when the Hepatitis C RIBA immunoblot assay is performed on the same sample, will be eligible to participate. Patients who are positive for Hepatitis C antibody and who have a positive or indeterminate result when the Hepatitis C RIBA immunoblot assay is performed on the same sample, will not be eligible to participate.
• HIV: known to have a historically positive HIV test or tests positive at screening for HIV.
• Immunodeficiency: recipient with a history of immunodeficiency (defined as Immunoglobulin A isotype (IgA) level <10 milligrams per deciliter (mg/dL) or have Immunoglobulin G isotype (IgG) level <400 mg/dL).
• Laboratory abnormalities: has an abnormal laboratory assessment, which is judged clinically significant by the investigator.
• Lymphopenia: has a lymphocyte count <500/ millimeter (mm)^3.
• Drug Sensitivity: has a history of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy including a previous anaphylactic reaction to parenteral administration contrast agents, human or murine proteins or monoclonal antibodies that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• Substance abuse: has evidence of current drug or alcohol abuse or dependence.
• Blood donation: where participation in the study would result in donation of blood or blood products in excess of 700 mL within a 56-day period
• Venous access: has venous access limitations likely to preclude monthly infusions
• Compliance: is unlikely to comply with scheduled study visits based on investigator judgment or has a history of substance abuse, psychiatric disorder or condition that may compromise communication with the investigator