Renal Function Evaluation After Reduction of Cyclosporine A Dose in Renal Transplant Patients
Condition: Kidney Transplantation; Primary Prevention; Kidney Failure
MeSH terms: Renal Insufficiency
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of the study is to show the efficacy of reduction of cyclosporine A exposure
      measured by the area under the curve by Bayesian estimator on the primary prevention of
      degradation of the renal function in renal transplant recipients
    

Detailed description: 
      Study population Eligible patients were 18 to 75 years of age and primary or secondary renal
      transplant recipients in their second year posttransplant with stable serum creatinine levels
      (i.e., < 20% variation for the previous 3 months). All patients must have received induction
      therapy, been corticosteroid-free for at least 3 months, and receiving combination
      maintenance therapy consisting of cyclosporine (trough level, 125 to 175 ng/mL) and
      mycophenolate mofetil (CellCept, F. Hoffmann- La Roche AG, Basel, Switzerland) 2 g daily.

      Patients at either low or high risk of graft dysfunction were ineligible; a majority of the
      participating centers maintained low immunological risk patients on cyclosporine alone and
      those with a high risk of graft dysfunction were usually maintained on corticosteroids. For
      this study, low risk was defined as the presence of the following: zero or one acute
      rejection episode with a return of renal function to previous levels after corticosteroid
      treatment, panel-reactive antibody titer <25%, serum creatinine level <125 µmol/L, age >25
      years, and donor age <40 years. High risk was defined as the presence of at least one of the
      following: a serum creatinine level >250 µmol/L, proteinuria >1 g/day, panel-reactive
      antibody titer >80%, >1 episode of T-cell-mediated rejection or at least one episode of
      antibody-mediated rejection posttransplant, or the presence of vasculitis or systemic lupus
      erythematosus which usually were treated with corticosteroids.

      Other exclusion criteria were evidence of systemic infection or malignancy within the
      previous 5 years (except adequately treated nonmetastatic basal or squamous cell carcinoma of
      the skin), leukocyte count <2.5x103/µL, hemoglobin <80 g/dL, platelet count <100x103/µL,
      severe intestinal disorders, pregnancy, breast feeding, current immunosuppressive treatment
      with drugs other than cyclosporine and mycophenolate mofetil. Women of childbearing age were
      required to use adequate contraception during treatment with mycophenolate mofetil and for
      six weeks after its discontinuation.

      Study Endpoints The primary endpoint was the proportion of patients with treatment failure
      (failure to prevent kidney dysfunction) at 24 months, which was a composite of graft loss,
      histologically confirmed acute rejection or cyclosporine toxicity, or a > 15% increase in the
      mean serum creatinine level from the baseline assessment. The mean of the current and two
      previous serum creatinine levels was used to determine the level at baseline, the level at
      the nadir (the time of the lowest serum creatinine measurement),and the level at 2 years.

      The secondary endpoints included the change in estimated glomerular filtration rate (eGFR)
      from baseline calculated using the four-variable equation from the Modification of Diet in
      Renal Disease (MDRD) Study; blood pressure, urinary protein, and lipid levels; severe adverse
      events such as infection requiring hospitalization, neoplasia, or lymphoma; and graft and
      patient survival.

      Study Follow-up and Procedures Weight, blood pressure after a 10-minute rest, serum
      creatinine and glucose levels, a complete blood cell count, and urinary protein levels were
      measured, and the use of immunosuppressive, antihypertensive, and lipid-lowering drugs was
      recorded at baseline and every 2 months. Serum lipid levels were measured at baseline and
      every 6 months. Gynecologic and dermatologic examinations were performed at baseline and
      yearly. Adverse events were recorded.

      Renal biopsies were performed when creatinine levels increased > 20% relative to the nadir or
      when proteinuria was >1 g/day. The nadir level was used as a reference point to obviate the
      risk of missing the diagnosis of rejection in the low-exposure arm; serum creatinine levels
      usually fell after the initiation of a low exposure regimen. Biopsies were classified using
      Banff 1997 criteria by four senior pathologists blinded to the clinical information.
      CNI-associated nephrotoxicity was graded mild, moderate, or severe according to the Banff
      1997 chronicity rejection scores.
    

Intervention name(s): cyclosporine A
Intervention type(s): Drug
Intervention description(s): The usual-exposure level was based on the mean area-under-the-concentration-time curve (AUC0-12h). In the usual-exposure group, the cyclosporine AUC0-12h target was 4.3 (3.5 to 4.8, range) mg•h/L and in the low-exposure group the target was 50% or 2.2 (2.0 to 2.6, range) mg•h/L. Ranges were asymmetrical for safety reasons, i.e., to prevent the occurrence of rejection in the low-exposure arm and nephrotoxicity in the usual-exposure arm.The AUC 0-12h was estimated using a Bayesian estimator and a three-point limited sampling strategy (0, 1, and 3 hours). A computer program was used to calculate the dose adjustment required to reach the therapeutic target. Doses were adjusted in increments of 25% to reach the target within 2 months. Cyclosporine AUC0-12h was determined every 2 months.
Other intervention name(s): cyclosporine microemulsion Neoral Novartis Basel Switzerland
Intervention MeSH terms: Cyclosporine; Cyclosporins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment