Clinical trial NCT00213590: Renal Function Evaluation After Reduction of Cyclosporine A Dose in Renal Transplant Patients
Official title: A Multicentric, Randomized, Opened Study to Evaluate Efficacy on Renal Function of an Immunosuppressant Regimen Based on Cyclosporine A Dose Reduction in Combination With Mycophenolate Mofetil, From the Second Year of Renal Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kidney Transplantation
Primary Prevention
Kidney Failure
Lead sponsor: University Hospital, Rouen
Sponsor class: OTHER
First posted: 2005-09-21
Enrollment: 208
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* first or second renal graft
* cadaveric renal graft
* second year of renal transplantation
* stable renal function
* moderate renal dysfunction risk
* bitherapy with cyclosporine A and mycophenolate mofetil
* corticosteroid withdrawal since 3 months at less

Exclusion Criteria:

* 2 or more acute rejection episodes
* PRA\> 80%
* serum creatinine\> 250µmol/L
* 24-hour proteinuria \> 1g
* humoral rejection
* vasculitis

Primary outcomes:
measure: renal function at two years
timeFrame: every two months
Secondary outcomes:
measure: proteinuria
timeFrame: every two months
measure: hypertension
timeFrame: every two months
measure: hemodialysis
timeFrame: at any time during the study period
measure: nephrotoxicity
timeFrame: at any time during the study period
measure: chronic renal dysfunction
timeFrame: at two years
measure: biopsy proven late acute rejection
timeFrame: at any time during the study period
measure: dyslipidemia
timeFrame: every six months
measure: patient survival
timeFrame: at two years
measure: graft survival
timeFrame: at two years
measure: severe infection with hospitalisation
timeFrame: at any time during the study period
measure: post transplant lymphoproliferative disorder
timeFrame: at any time during the study period
measure: cutaneous carcinoma
timeFrame: every year
measure: area under the concentration-time of cyclosporine A
timeFrame: every two months
measure: area under the concentration-time of mycophenolate mofetil
timeFrame: at month 0 6 12 and 24
measure: biodisponibility of mycophenolate mofetil after reduction of cyclosporine A exposure
timeFrame: at month 6 12 and 24
Other outcomes:
Locations:
Study officials:
affiliation: University Hospital, Rouen
name: Isabelle ETIENNE, MD
role: PRINCIPAL_INVESTIGATOR
References: