Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00188955
Status:
COMPLETED
Last Update Posted:
2010-02-22
First Post:
2005-09-10
Brief Title:
Pilot Study on the Use of Sirolimus to Treat Chronic Allograft Nephropathy in Children After Kidney Transplant
Sponsor:
University of Manitoba
Organization:
University of Manitoba
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2010-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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 mgm2 in 2 divided doses 15 mgm2dose bid on study day 1 Beginning on study day 2 patients will receive 1mgm2day orally in divided doses 05 mgm2dose 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 ngml and 12 ngml
Patients randomized to Group B will continue to receive MMF 1200 mgm2day orally in divided doses 600 mgm2dose 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 20 mgml and 40 mgml
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 proteincreatinine 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 Students 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 005 is considered significant
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 mgm2 in 2 divided doses 15 mgm2dose bid on study day 1 Beginning on study day 2 patients will receive 1mgm2day orally in divided doses 05 mgm2dose 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 ngml and 12 ngml
Patients randomized to Group B will continue to receive MMF 1200 mgm2day orally in divided doses 600 mgm2dose 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 20 mgml and 40 mgml
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 proteincreatinine 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 Students 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 005 is considered significant
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None