A Study Looking at Kidney Function in Kidney Transplant Recipients Who Are Taking Anti-rejection Medication Including Tacrolimus and With or Without Sirolimus. (ADHERE)

• Efficacy failure [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
  Composite endpoint defined as graft loss (re-transplantation, nephrectomy, death or dialysis ongoing at the study end) or subject withdrawal
• GFR at Week 52 post kidney transplantation by Modification Diet in Renal Disease (MDRD) formula [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• GFR at Week 52 post kidney transplantation by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Calculated creatinine clearance at Week 52 post kidney transplantation by Cockcroft and Gault formula [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Incidence of clinical acute rejection [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Time to clinical acute rejection [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Incidence of Biopsy Confirmed Acute Rejection [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Time to Biopsy Confirmed Acute Rejection [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Subject survival [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Graft survival [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• New Onset Diabetes Mellitus (NODM) as per American Diabetic Association (ADA) criteria [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]

The purpose of this study is to compare the effect of two anti-rejection therapy regimens on kidney function in kidney transplant recipients.

This study will evaluate the potential to reduce nephrotoxic calcineurin inhibitors (CNI) therapy by lowering tacrolimus exposure from Advagraf® in combination with the non-nephrotoxic immunosuppressant sirolimus to avoid the risk of acute graft rejection, compared with an Advagraf® and Mycophenolate Mofetil (MMF) immunosuppressive regimen.

• Drug: Advagraf
  oral
  Other Names:

  • Prolonged release tacrolimus
  • FK506E
• Drug: Mycophenolate Mofetil
  oral
  Other Name: CellCept
• Drug: Sirolimus
  oral
  Other Name: Rapamune
• Drug: Corticosteroids
  i.v. and oral

• Active Comparator: Advagraf + MMF + Steroids
  Without sirolimus
  Interventions:

  • Drug: Advagraf
  • Drug: Mycophenolate Mofetil
  • Drug: Corticosteroids
• Experimental: Advagraf + MMF + Steroids + Sirolimus
  With sirolimus; MMF withdrawn on Day 28; Sirolimus introduced on Day 28
  Interventions:

  • Drug: Advagraf
  • Drug: Mycophenolate Mofetil
  • Drug: Sirolimus
  • Drug: Corticosteroids

Inclusion Criteria:

• End stage kidney disease and a suitable candidate for primary renal transplantation or re-transplantation (unless the graft was lost from rejection within 6 months)
• Receiving a kidney transplant from a deceased or living (non Human Leukocyte Antigen [HLA] identical) donor with compatible ABO blood type
• Female subject of childbearing potential has a negative serum or urine pregnancy test at enrollment
• Female and male subjects agree to maintain highly effective birth control during the study and for 90 days after discontinuation of dosing with study drugs. A highly effective method of birth control is defined as those which result in a low failure rate (CPMP/ ICH/ 286/ 95 modified) of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some Intrauterine Devises (IUDs), sexual abstinence or vasectomized partner

Exclusion Criteria:

• Receiving or having previously received an organ transplant other than a kidney
• Cold ischemia time of the donor kidney > 30 hours
• Panel Reactive Antibody (PRA) >20%
• Receiving a graft from a non-heart-beating donor other than of Maastricht category 3 (withdrawal of support awaiting cardiac arrest)
• Significant liver disease, defined as having continuously elevated SGPT/ ALT and/ or SGOT/ AST and/ or total bilirubin levels ≥ 2 times the upper value of the normal range of the investigational site or is receiving a graft from a hepatitis C or B positive donor
• Requiring initial sequential or parallel therapy with immunosuppressive antibody preparation(s)
• Requiring ongoing dosing with a systemic immunosuppressive drug prior to transplantation (other than minimal levels of immunosuppression following failure of previous transplantation without nephrectomy)
• Significant, uncontrolled concomitant infections and/ or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer
• Pregnant woman or breast-feeding mother
• Subject or donor known to be HIV positive
• Known allergy or intolerance to tacrolimus, macrolide antibiotics, corticosteroids, sirolimus, MMF or any of the product excipients or iodine
• Evidence of malignant disease within the last 5 years, not including non-malignant skin cancers
• Currently participating in another clinical trial, and/ or has taken an investigational drug within 28 days prior to enrollment
• Unlikely to comply with the visits scheduled in the protocol