Kidney Transplantation Clinical Trial
Official title:
Phase 4 Randomized, Controlled Study Comparing Sirolimus and Mycophenolate Mofetil to Prevent or Reverse Progression in Pediatric Renal Transplants With Chronic Allograft Nephropathy
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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