The most common problem following a kidney transplant is the development of acute or chronic
rejection. Rejection is the immunologic reaction in which the body refuses to accept the
transplanted organ. The body's immune system will make destructive antibodies that will
attempt to attack the transplanted organ.
In order to prevent organ rejection, all patients receiving an allograft (a graft
transplanted between genetically non-identical individuals of the same species) must take
anti-rejection therapy. These medications function by lowering the body's natural immune
system. Often these medications are associated with significant side effects ranging from
infections to cancer.
This study is designed to test whether the drug presently known as BG9588 (Antova TM) can
reduce the incidence of organ rejection following kidney transplants in humans. More
specifically, the study will attempt to assess the safety of BG9588 when given alone or when
given in combination with other anti-rejection therapies. Safety will be measured by the
amount of acute or chronic rejections, and immunological graft losses.
Subjects for the study will be made up of non-human primates (monkeys) and humans. Up to 5
subjects in each of the groups receiving kidney transplants will be placed on a 12 month
course of BG9588 with or without additional anti-rejection drugs. BG9588 will be given
intravenously (injected through a vein) prior to the transplant and then in a decreased dose
with a decreased frequency over the year. Following the 12 months of therapy subjects may
be eligible for additional monthly therapy.
The long-term follow up will occur through 30 months after the last dose of BG9588.
Subjects will undergo periodic tests and evaluations throughout the course of the study.
These tests will assess the body's immune system and detect the presence of rejection.
This protocol is an open label, non-randomized study designed to test whether treatment with
BG9588, a humanized monoclonal antibody specific for CD154, can induce a state of allograft
tolerance following renal allotransplantation in humans. This study is designed to
primarily assess the safety and efficacy of BG9588 when given alone or in combination with
steroids and mycophenolate to prevent renal allograft rejection without the use of
calcineurin inhibitors or other chronic anti-rejection therapies. Efficacy parameters will
include the incidence of acute and chronic rejection episodes, and immunological graft loss.
Additional evaluation will be performed to specifically assess the development of
donor-specific immune hyporesponsiveness resulting from the use of BG9588.
This study is based on extensive use of BG9588 in non-human primates and pilot evaluation in
humans. Up to five patients in each group receiving primary renal allografts will be
treated with a 12-month course of BG9588 with or without steroids and mycophenolate to
prevent allograft rejection. The recruitment will be performed first in the group with
steroids and mycophenolate. Subjects will receive BG9588 at a dose of 70 mg/kg (based on
ideal body weight at baseline) via a continuous 60 minute IV infusion within 24 hours
pre-operatively followed by a 30 mg/kg dose via a continuous 30 minute IV infusion on the
following days: within 24 hours post-transplantation, and on days 3, 10, 18, 28, then
monthly through 12 months post-transplantation. The enrollment will be staggered such that
early efficacy will be demonstrated in 5 patients prior to completing enrollment. Following
12 months of therapy, patients may be extended to receive additional monthly therapy.
Long-term follow up will occur through 30 months after the last dose of BG9588. Mechanistic
evaluations testing for allograft tolerance will be performed throughout the study including
evaluations for allospecific T cell deletion, allospecific T cell anergy, and alloantibody
production. The donor population for this study will include both living donors and
cadaveric donors. This is being done to address the theoretical concern that ischemic
reperfusion injury may negatively affect the efficacy of BG9588.
Must be a candidate for a renal transplant from a living related, living non-related, or
Must be willing and able to give written informed consent.
Aged between 18 and 65 years, inclusive. Subjects over the age of 65 may be considered on
an individual basis based on medical suitability.
Female subjects must be post-menopausal or surgically sterile, or using an acceptable
method of contraception (oral contraceptives, Norplant, Depo-Provera, and barrier devices
are acceptable; condoms used alone are not acceptable).
WBC count must be greater than or equal to 3000/mm(2).
No history of malignancy (except non-metastatic cutaneous squamous or basal cell
carcinomas that have been completely excised without evidence of recurrence for at least 1
No active systemic bacterial, fungal or viral infections (including active zoster or
No serological evidence of HIV, HCV, or HbsAg.
No active peptic ulcer disease.
No condition or circumstance that could potentially interfere with the evaluation of
No contraindication to monoclonal antibody therapies.
No history of Major Thromboembolic event (e.g. stroke, pulmonary embolus).
For the first 5 patients, no patient with a PRA greater than 20%.
No previous participation in the study.
No use of any investigational agent or device within 4 weeks prior to first dose of study
No Cold Ischemia Time of donor kidney greater than 36 hours.
No uncontrolled non-heart-beating donor status.
No positive T-cell Crossmatch.