Pilot Study on the Use of Sirolimus to Treat Chronic Allograft Nephropathy in Children After Kidney Transplant
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|ClinicalTrials.gov Identifier: NCT00188955|
Recruitment Status : Completed
First Posted : September 16, 2005
Last Update Posted : February 22, 2010
|First Submitted Date ICMJE||September 10, 2005|
|First Posted Date ICMJE||September 16, 2005|
|Last Update Posted Date||February 22, 2010|
|Study Start Date ICMJE||March 2004|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||histological quantification of interstitial fibrosis at 2 years|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00188955 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Pilot Study on the Use of Sirolimus to Treat Chronic Allograft Nephropathy in Children After Kidney Transplant|
|Official Title ICMJE||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.
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:
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 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.
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Kidney Transplantation|
|Intervention ICMJE||Drug: sirolimus|
|Study Arms ICMJE||Not Provided|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Original Enrollment ICMJE||Same as current|
|Actual Study Completion Date ICMJE||October 2008|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages ICMJE||6 Years to 18 Years (Child, Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT00188955|
|Other Study ID Numbers ICMJE||WINNIPEG-CAN-1|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||University of Manitoba|
|Collaborators ICMJE||Wyeth is now a wholly owned subsidiary of Pfizer|
|PRS Account||University of Manitoba|
|Verification Date||February 2010|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP