Study Evaluating Conversion From Tacrolimus to Sirolimus in Stable Kidney Transplant Recipients Receiving Myfortic

A Pilot Study to Evaluate the Safety and Efficacy of Mycophenolate Sodium (Myfortic®) in Combination With Sirolimus (Rapamune®) in Stable Renal Allograft Recipients

The purpose of this study is to determine whether the combination of Myfortic and sirolimus is effective at preventing rejection while preserving kidney function in stable kidney transplant recipients.

One-year graft survival after renal transplantation dramatically improved with the addition of calcineurin inhibitors (tacrolimus or cyclosporine) to maintenance immunosuppression regimens. Much of this improvement in early graft survival has been attributed to the efficacy of the calcineurin inhibitors in preventing early acute rejection episodes. However, long-term graft survival has not improved to as great of a magnitude as the improvements in short-term survival. In addition, research shows progressive decline in kidney function throughout the years post-transplantation. Clinical research now focuses on improving long term graft survival while maintaining long-term kidney function.

The leading cause of graft loss has been attributed to chronic allograft nephropathy (CAN). Risk factors for CAN include: prolonged ischemia time, delayed graft function, acute rejection episodes and calcineurin inhibitor nephrotoxicity (CIN). CIN has been identified as the most common identifiable contributor to CAN and the chief cause of late histologic injury and ongoing decline in renal function. At 10 years post-transplant, CIN has been found to be universally prevalent.

Calcineurin inhibitor minimization and elimination studies have sought to improve long-term allograft function by minimizing exposure to these nephrotoxic agents. Studies have demonstrated that early withdrawal of cyclosporine from a cyclosporine, sirolimus and steroid immunosuppression regimen at 3 months post-transplant improved renal function and graft survival at 48 months post-transplant. Other studies have demonstrated diminished prevalence of CAN at 2 years post-transplant in those patients maintained on sirolimus as compared with cyclosporine. Kidney function was also significantly improved with lower serum creatinine and higher GFR in the sirolimus maintenance group.

Sirolimus is a macrolide antibiotic immunosuppressive agent that exerts its mechanism of action by inhibiting the mTOR signaling cascade. In clinical trials, sirolimus was found to lack nephrotoxic effects when compared to cyclosporine. In kidney transplantation, multiple studies have demonstrated safety and efficacy of sirolimus in calcineurin inhibitor avoidance and withdrawal protocols.

Myfortic® (mycophenolate acid) is an enteric coated formulation of mycophenolic acid (MPA) approved for the prevention of rejection in kidney transplant recipients in combination with cyclosporine and corticosteroids. Myfortic® has no documented nephrotoxic effects. Mycophenolate mofetil (MMF), a prodrug of MPA also does not demonstrate nephrotoxic effects. Early studies have demonstrated therapeutic equivalence between Myfortic® and MMF both in de novo renal transplants and in conversion studies where MMF is converted to Myfortic at least 6 months after renal transplantation. Thus, studies demonstrating safety and efficacy of MMF with sirolimus in calcineurin inhibitor withdrawal protocols should also hold true using Myfortic® in such regimen.

This study will assess the safety and efficacy of Myfortic® when used in a simultaneous sirolimus conversion and calcineurin inhibitor withdrawal regimen in stable renal transplant recipients. Study subjects will receive immunosuppression consisting of Myfortic®, tacrolimus and corticosteroids (prednisone) starting the day of transplant. Conversion from tacrolimus (Prograf) to sirolimus (Rapamune) will occur between 90 and 180 days post cadaver-donor or living-donor renal transplant. All participants will be converted from tacrolimus to sirolimus and remain on Myfortic® and their current corticosteroid taper.

Inclusion Criteria I (-1 to 7 days post renal allograft transplant):

• Male or female patient 18 years of age or older.
• Patient has been fully informed of study procedures and requirements, has signed an IRB approved consent form and is willing and able to follow study procedures.

Exclusion Criteria I (-1 to 7 days post renal allograft transplant):

• Patient has previously received an organ transplant.
• Patient has an identified donor specific antibody prior to transplant
• Patient is known to be seropositive for the human immunodeficiency virus (HIV).
• Patient has active Hepatitis C or B infection documented by a positive DNA PCR. Patients who are seropositive for Hepatitis C virus (HCV) or B virus (HBV) but have negative HCV-RNA or HBV-DNA by PCR may be included.
• Patient has a current malignancy or a history of malignancy within the past 5 years, except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully.
• Patient has an uncontrolled infection or unstable medical condition that could interfere with the study objectives.
• Patient is currently taking or has been taking an investigational drug in the past 30 days.
• Patient has a known hypersensitivity to sirolimus or Myfortic®.
• Patient is pregnant or lactating.
• Patient is unlikely to comply with the visits scheduled in the protocol.
• Patient has any form of substance abuse, psychiatric disorder or a condition that, in the opinion of the investigator, may invalidate communication with the investigator.

Inclusion Criteria II (90 - 180 days post renal allograft transplant):

• Patient is 90 to 180 days after having received a primary living- or cadaver-donor renal allograft
• Patient has been maintained on a regimen of tacrolimus, Myfortic® and corticosteroids prior to study enrollment.
• Patient has a stable allograft defined as calculated GFR > 30 mL/min using Nankivell equation.
• Patient has been fully informed of study procedures and requirements, has signed an IRB approved consent form and is willing and able to follow study requirements.
• Female patients of child bearing potential must use at least one reliable form of contraception unless they are status post bilateral tubal ligation, bilateral oophorectomy or hysterectomy. Effective contraception must be used for the duration of the study.

Exclusion Criteria II (90 - 180 days post renal allograft transplant):

• Patient has experienced an acute graft rejection of ≥ Banff '97 1b or humoral rejection as determined by biopsy within the first 90 days post-transplant
• Patient has experienced an acute graft rejection of ≤ Banff 97 1a as determined by biopsy within 30 days prior to Baseline visit.
• Patient has untreated hypercholesterolemia defined as triglycerides > 300 or total cholesterol >200 within the previous 30 days.
• Patient is currently (< 7 days) leukopenic defined as WBC < 3,000 cells/mL or thrombocytopenic defined as platelets < 100,000 cells/mL.
• Patient has significant liver disease, defined as having during the past 30 days continuously elevated AST (SGOT) and/or ALT (SGPT) levels greater than 3 times the upper value of normal range.