Early Conversion From Tacrolimus to Efalizumab Maintenance Therapy in Kidney Transplant Recipients

Study Overview
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Brief Summary
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The toxicity of calcineurin inhibitors(CNI)is a major factor limiting the success of renal transplantation. This protocol aims to replace the calcineurin inhibitor, tacrolimus, with efalizumab early after transplantation in patients with mild impairment of renal function in order to minimize the toxicities of CNI.

Detailed Description
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Over the last two decades there have been significant improvements in renal transplantation due in large part to the decreasing incidence of acute rejection (down to less than 20% for first renal transplants) with the use of calcineurin inhibitors (CNI) such as cyclosporin and tacrolimus. Though proven very effective anti-rejection medications their use is associated with adverse side effects, including high blood pressure, post transplant diabetes, and high cholesterol, predisposing risk factors for cardiovascular disease and cerebrovascular disease. Chronic use of these drugs has also waged limitations to the long term survival of transplanted kidneys and kidney recipients with an increase in the development of chronic allograft nephropathy (CAN). There is also an increased incidence of chronic renal failure in non renal transplant recipients receiving CNI based treatments. The mechanism of action for these reagents is known to be imprecise and science has sought to replace the current therapies in place with less toxic drugs more specific in their signaling pathway targets. In recent years cell surface proteins, restricted to cells of the immune system have been identified as mediators of the rejection response. The activation of T cells has been seen to activate an immune response correlated clinically with rejection. Integrins, specifically leukocyte function associated antigen LFA-1, are cell surface molecules which play a role in T-cell activation. LFA-1 is made up of two subunits, known as CD11 and CD18. Efalizumab is a humanized monoclonal antibody against the CD11 molecule. By binding to CD11 on T cells the system blocks the interaction between LFA-1 and ICAM-1, an intercellular adhesion molecule also necessary for T cell activation, thereby diminishing an immune response. The blockade formed does not deplete the T cells. There have been preliminary studies using efalizumab in combination with cyclosporine. A very low incidence of rejection was observed in all groups receiving efalizumab (7.8%). However 3 cases of post-transplant lymphoproliferative disease were seen in 38 patients. There have been no cases of lymphomas or lymphoproliferative disease reported in clinical trials evaluating efalizumab for the treatment of psoriasis, suggesting that the combination of efalizumab and cyclosporine may have resulted in over immunosuppression. As per standard of care, recipients of a kidney transplant at Emory are managed with a combination of the calcineurin inhibitor Prograf (tacrolimus), Cellcept (an antiproliferative agent) and Prednisone, a corticosteroid. For this study the investigators have chosen to substitute efalizumab in place of Prograf, after 3 months post transplant the period where the incidence of acute rejection is highest. Efalizumab, known by its trade name Raptiva, was approved by the FDA in October 2003 for the treatment of psoriasis. It is hypothesized that the conversion from Prograf to efalizumab will be associated with improved renal function and not associated with an increased risk of rejection. The investigators hope to address the challenges faced by recipients of transplanted kidneys in the long course of their transplanted organ's management with more favorable alternatives.

Official Title
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An Open Label, Single-Center Pilot Study of Early Conversion From Tacrolimus to Efalizumab Maintenance Therapy in Primary Renal Transplant Recipients

Conditions
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Kidney Transplantation, Chronic Kidney Failure

Intervention / Treatment
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* Drug: efalizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary renal transplant recipients recipients of deceased donor or living donor transplant Age 18-65 years (inclusive) Male or female Within 3-9 month window post-transplantation No episodes of acute rejection prior to enrollment Mild impairment of renal function as defined by a calculated CrCl of 35-50 ml/min/m2 Exclusion Criteria: Subjects with any prior solid organ transplant (including kidney) Subjects with a history of panel-reactive antibodies greater than 20% or the development of new anti-HLA antibodies after transplantation and prior to enrollment Subjects the Investigator deems to be at a relatively higher risk for acute rejection HLA-identical living donor pairs Evidence of infection with Hepatitis C (antibody positive or PCR positive), Hepatitis B ( surface antigen positive), HIV Subjects with BK or CMV viremia prior to enrollment Multiple organ transplant recipients Subjects with underlying renal disease of focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, hemolytic-uremic syndrome/thrombocytopenic purpura syndrome (due to risk of rapid disease recurrence in the allograft EBV negative recipients Women who are pregnant or nursing Women of child bearing age unwilling or unable to use an acceptable method to avoid pregnancy for the duration of the study and up to 8 weeks after last injection Patients not able to tolerate a dose of at least 500 mg of mycophenolate mofetil twice daily Allergy to Iodine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>The study drug Efalizumab will be given as part of a triple drug regimen including mycophenolate mofetil and prednisone. A test dose of Efalizumab 0.7mg/kg will be given at the enrollment visit. Beginning with study visit 2, Efalizumab 1mg/kg will be administered subcutaneously by injection on a weekly basis for 1 year. Mycophenolate mofetil will be given at a dose of 2gm/day which is the same as the standard of care dose. If patient experiences drug toxicity with mycophenolate mofetil they may be reduced and resume a minimum of at least 1gram daily to continue in the study. Patients will be maintained at 10mg of prednisone daily, same as standard of care. | Drug: efalizumab<br>* Administration of a test dose of efalizumab 0.7mg/kg will be administered at enrollment. Weekly subcutaneous injections of efalizumab 1mg/kg will begin with study visit 2 and continue for 1 year for this pilot study.<br>* Other names: Raptiva is the brand name FDA approved for the treatment of psoriasis.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy Will be Determined by Change in Renal Function as Measured by Cold Iothalamate Glomerular Filtration Rate(GFR)3 Months After Enrollment, and Acute Rejection Episodes Within the First 6 Months Post Enrollment. |  | 6 months from conversion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, Including Incidence of Post- Transplant Infections, Malignancies, Morbidities, Hypertension, Glucose Intolerance, Serum Cholesterol and Triglycerides Profile Over Time, Development of New Anti-donor Antibodies. |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppression, Renal Transplantation