Pilot Study on the Use of Sirolimus to Treat Chronic Allograft Nephropathy in Children After Kidney Transplant
Condition: Kidney Transplantation
MeSH terms: Kidney Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine whether treatment with sirolimus, in combination
      with low-dose tacrolimus and prednisone, is effective for the treatment of chronic allograft
      nephropathy (progressive scarring) in children who have previously received a kidney
      transplant. This treatment is compared to the standard therapy which uses low-dose
      tacrolimus, mycophenolate mofetil and prednisons.

      This study is a pilot study that will determine whether treatment with sirolimus reduces or
      improves the rate of scarring seen on kidney biopsy of the transplanted kidney over time,
      compared to children who continue to be treated with mycophenolate mofetil.
    

Detailed description: 
      PROTOCOL SYNOPSIS

      Title Of Study: A Single Center, Prospective, Randomized, Controlled Study Of Two Chronic
      Immunosuppressive Protocols Using Sirolimus Or Mycophenolate Mofetil To Prevent Or Reverse
      Disease Progression In Pediatric Renal Transplants With Chronic Allograft Nephropathy

      Short Title: Winnipeg-CAN-1

      Clinical Trial: Phase-IV

      Objectives: This prospective, randomized, controlled study will evaluate the effectiveness of
      two different chronic immunosuppressive protocols in the treatment of chronic allograft
      nephropathy (CAN) in children. One protocol will continue with standard immunosuppression
      which includes mycophenolate mofetil (MMF), and the other will substitute MMF with sirolimus.

      The primary objective is as follows:

      · To evaluate the effectiveness of treatment with sirolimus in pediatric renal transplant
      recipients with established CAN compared to MMF at reducing the rate of progression of CAN as
      measured by prospective histological evaluation of sequential kidney biopsies using
      quantification of interstitial fibrosis by image analysis and a validated standardized
      scoring schema (Banff 97 criteria).

      The secondary objectives are as follows:

        -  To evaluate the effectiveness of treatment with sirolimus in pediatric renal transplant
           recipients with established CAN compared to MMF at slowing the rate of clinical
           deterioration associated with progression of CAN as measured by the change of serum
           creatinine and corrected glomerular filtration rate (GFR) over the study period.

        -  To analyze the effect of treatment with sirolimus in pediatric renal transplant
           recipients with established CAN compared to MMF on the incidence of late AR as
           identified by prospective histological evaluation of sequential kidney biopsies.

        -  To analyze the effect of treatment with sirolimus in pediatric renal transplant
           recipients with established CAN compared to MMF on the incidence graft failure as
           defined by a return to dialysis, re-transplantation or death from uremic complications.

        -  To analyze the differences in the expression of molecular markers of fibrosis in
           pediatric renal transplant recipients with established CAN treated with sirolimus
           compared to MMF by immunohistochemical identification of extracellular matrix protein
           expression and remodeling and quantification by image analysis.

      Study Design: The study will be a prospective, single-centre, randomized, controlled trial in
      pediatric patients with functioning kidney transplants who have biopsy-proven CAN. The study
      is designed to compare the efficacy of two chronic immunosuppression regimens intended for
      the treatment of CAN. Patients (aged 1-17 years) who have CAN demonstrated on protocol biopsy
      or on biopsy done for clinical suspicion of CAN, will be considered for enrollment. Eligible
      patients will be enrolled and treatment will be randomized between one of two treatment
      groups: Group A will receive sirolimus in combination with low-dose tacrolimus and
      prednisone; Group B will receive the current local standard therapy, which is MMF, low-dose
      tacrolimus and prednisone. All other transplant care will be according to standard local
      practice.

      Study participants will be followed for a period of 2 years, and will undergo protocol
      biopsies at 1 and 2 years. The timing of these biopsies will coincide with already planned
      protocol biopsies. Clinical, laboratory and histological data will be gathered prospectively
      to determine efficacy according to pre-defined criteria measuring the extent of CAN and
      interstitial fibrosis. Study visits will coincide with routine clinic visits, except for
      weekly visits at the study onset to titrate drug dosing according to trough levels. Blood and
      urine tests, blood pressure monitoring, timed urine collections and nuclear GFR testing will
      be performed according to the normal clinical care protocols. Additional pharmacokinetic
      testing will occur at 3 and 12 months.

      Participants will be enrolled over a 2-year period and will be followed according to study
      protocol for 2 years. 40 patients will be enrolled.

      Dosages, Route and Dose Regimen:

      Patients randomized to Group A will receive an initial oral loading dose of sirolimus 3 mg/m2
      in 2 divided doses (1.5 mg/m2/dose bid) on study day 1. Beginning on study day 2, patients
      will receive 1mg/m2/day orally in divided doses (0.5 mg/m2/dose) every 12 hours. Therapeutic
      drug monitoring of 12-hour trough concentrations will be performed at weeks 1-4, then monthly
      for the first 3 months, then at least every 3 months, and dose adjustments will be made in
      order to achieve 12-hour trough levels between 8 ng/ml and 12 ng/ml.

      Patients randomized to Group B will continue to receive MMF 1200 mg/m2/day orally in divided
      doses (600 mg/m2/dose) every 12 hours starting on Study Day 1. Therapeutic drug monitoring of
      12-hour trough concentrations will be performed at weeks 1-4, then monthly for the first 3
      months, then at least every 3 months, and dose adjustments will be made in order to achieve
      12-hour trough mycophenolic acid (MPA) levels of between 2.0 mg/ml and 4.0 mg/ml.

      Safety Measurements:

      Safety will be determined by monitoring AEs, vital signs, and laboratory parameters (clinical
      chemistry, hematology, and urinalysis) during the follow-up period. In particular, signs and
      symptoms associated with known medication side effects such as infection, malignancy, anemia
      (sirolimus), thrombocytopenia (sirolimus), hyperlipidemia (sirolimus), leukopenia (MMF) and
      GI effects (MMF). Serial monitoring of renal function will indicate acute rejection or drug
      toxicity, to be confirmed on biopsy.

      Primary Efficacy And Secondary Endpoints:

      Quantitative changes in CAN will be used to determine efficacy. Protocol renal allograft
      biopsies will be performed at 12 and 24 months after study enrollment and will be compared to
      the baseline histology obtained from routine protocol surveillance biopsy during the
      screening period which are performed at 1, 3, 6 12 months post-transplant, and yearly
      thereafter. The amount of CAN will be measured by semi-quantitative scoring of histological
      changes characteristic of CAN according to the Banff 97 schema, and interstitial fibrosis
      will be quantified using image analysis.

      Secondary endpoints include changes of renal function, proteinuria, rates of acute rejection,
      graft survival, and the expression of proteins important in interstitial matrix remodelling
      by immunohistochemistry. Renal function will be monitored at each clinical visit and will be
      compared with baseline function over the duration of the study. In addition, quantitative
      assessment of GFR corrected for body surface area will be obtained at baseline, 1 and 2
      years, by nuclear GFR measurement. Proteinuria will be quantified by 24-hour urine collection
      at baseline and every 6 months during the study or by spot protein:creatinine ratio.

      Statistical Analysis:

      Data are expressed as mean ± standard deviation. Quantitative TFR will be compared between
      groups using the change in TFR over time (DTFR) and the percent change from baseline (%DTFR).
      The Student's t-test will be used to compare the change between groups for the primary
      endpoint. One-way ANOVA will be used to detect significant change for multiple time-points,
      and multiple ANOVA to examine correlation between interval variables. Multiple regression
      analysis is used to determine the predictive value of different, possibly independent
      quantitative variables. Non-parametric variables will be analyzed using the Wilcoxon Signed
      Rank Test, and treatment differences over time using the Quade test. A difference of <0.05 is
      considered significant.
    

Intervention name(s): sirolimus
Intervention type(s): Drug
Intervention MeSH terms: Sirolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: pediatric; chronic allograft nephropathy; chronic rejection; interstitial fibrosis