Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00193635
Status:
COMPLETED
Last Update Posted:
2007-10-19
First Post:
2005-09-09
Brief Title:
Pilot Study of Mycophenolate Mofetil in Congenital Uropathies
Sponsor:
Northwell Health
Organization:
Northwell Health
Study Overview
Official Title:
Pilot Study of Mycophenolate Mofetil in Congenital Uropathies
Status:
COMPLETED
Status Verified Date:
2007-10
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:
Congenital or hereditary structural anomalies of the genitourinary tract account for approximately half of all cases of end stage renal disease in the pediatric population Despite optimal medical management when the GFR falls below 50 mlmin173 M2 nearly 40 of affected children will require dialysis or a renal transplant within 2 years At present there is no specific treatment for patients with congenital uropathies that can retard the progressive loss of kidney function and forestall the need for renal replacement therapy
There is evidence in experimental animals and in patients with chronic renal failure CRF that immunoeffector mechanisms are activated within the renal parenchyma Infiltration of the kidney by macrophages monocytes and lymphocytes activation of renal tubular epithelial cells and release of pro-inflammatory cytokines result in fibrosis and irreversible organ damage
Mycophenolate mofetil MMF is a new immunosuppressive agent that is used to prevent acute rejection in kidney transplant recipients It attenuates renal damage in the remnant kidney model of CRF in which there is no primary immunological injury Therefore this pilot study is designed to test the hypothesis that immunosuppressive treatment with MMF in children with structural causes of CRF will be safely tolerated and that this therapy will retard progressive decline in renal function
Patients with congenital uropathy 3-16 years of age and with a GFR less than 50 mlml173 M2 will be treated with MMF for 24 months The two primary endpoints are 1 safety and tolerance of the drug and 2 need for dialysis or kidney transplantation It is anticipated that the MMF will be free of significant toxicity and that administration of the drug will reduce the frequency of progression to end stage renal disease from 38 to 19 Patients will be followed at 3-month intervals and they will undergo serial assessment of proteinuria estimated GFR and iothalamate clearance urinary cytokine excretion urine flow cytometry and immunologic testing
The significance of this pilot study is that it may provide evidence in support of a randomized double-blind placebo-controlled trial of immunological treatment of congenital structural causes of CRF in children
There is evidence in experimental animals and in patients with chronic renal failure CRF that immunoeffector mechanisms are activated within the renal parenchyma Infiltration of the kidney by macrophages monocytes and lymphocytes activation of renal tubular epithelial cells and release of pro-inflammatory cytokines result in fibrosis and irreversible organ damage
Mycophenolate mofetil MMF is a new immunosuppressive agent that is used to prevent acute rejection in kidney transplant recipients It attenuates renal damage in the remnant kidney model of CRF in which there is no primary immunological injury Therefore this pilot study is designed to test the hypothesis that immunosuppressive treatment with MMF in children with structural causes of CRF will be safely tolerated and that this therapy will retard progressive decline in renal function
Patients with congenital uropathy 3-16 years of age and with a GFR less than 50 mlml173 M2 will be treated with MMF for 24 months The two primary endpoints are 1 safety and tolerance of the drug and 2 need for dialysis or kidney transplantation It is anticipated that the MMF will be free of significant toxicity and that administration of the drug will reduce the frequency of progression to end stage renal disease from 38 to 19 Patients will be followed at 3-month intervals and they will undergo serial assessment of proteinuria estimated GFR and iothalamate clearance urinary cytokine excretion urine flow cytometry and immunologic testing
The significance of this pilot study is that it may provide evidence in support of a randomized double-blind placebo-controlled trial of immunological treatment of congenital structural causes of CRF in children
Detailed Description:
Sustained activation of the immune system may contribute to progressive renal injury in all forms of chronic kidney disease There is extensive proliferation of renal tubular epithelial cells and fibroblasts within the kidney of patients with chronic renal failure CRF The fibroblasts manifest an activated myofibroblast phenotype evidenced by expression of alpha smooth muscle actin This change is accompanied by infiltration of the renal interstitium with macrophages lymphocytes and other immunocompetent cells The cells are also activated and release numerous cytokines and inflammatory mediators These substances exacerbate the injury process by recruiting additional immunoeffector cells into the kidney parenchyma and stimulating the production and secretion of pro-inflammatory molecules These findings suggest that immunosuppressive medications may be beneficial in the treatment of congenital uropathies In fact mycophenolate mofetil MMF 10-30 mgkgday has been given to rats that had been subjected to a 56 nephrectomy Uremia in this remnant kidney model is not the consequence of primary immunological disease MMF treatment for 30-60 days did not prevent intraglomerular hypertension or the alterations in renal hemodynamics that characterize the adaptation to reduced renal mass However the extensive infiltration of the renal interstitium by proliferating lymphocytes was markedly attenuated by MMF treatment Moreover despite the relatively selective anti-metabolic effect of MMF on lymphocytes there was a significant reduction in macrophage infiltration in the tubulointerstitium This beneficial change was associated with a significant reduction in albuminuria and glomerulosclerosis after 60 days of MMF treatment Combined treatment with the MMF and the angiotensin converting enzyme ACE inhibitor lisinopril to rats with reduced renal mass diminished tubulointerstitial infiltration by macrophages and T cells even more than MMF therapy alone and nearly normalized urinary protein excretion Thus pharmacological treatment with MMF attenuated the progression of nonimmunological renal disease in the remnant kidney model without favorably impacting on intraglomerular hemodynamics or the hypertrophic response to peptide growth factors
MMF is a well-tolerated safe and effective immunosuppressive medication in adult and pediatric recipients of cadaveric and living-related renal transplants
HYPOTHESIS AND SPECIFIC AIMS This open-label pilot study is designed to test the hypothesis that there is sustained activation of immunoeffector systems that mediate progressive loss of renal function in children with congenital uropathies Immunosuppressive therapy can inhibit this process and retard the rate of decline in kidney function in pediatric patients with structural non-immunological kidney conditions
Specific Aim1 Determine whether administration of mycophenolate mofetil MMF to pediatric patients with a glomerular filtration rate GFR 50 mlminm2 due to congenital uropathies such as dysplasiahypoplasia obstructive uropathy and reflux nephropathy is safe and well tolerated
Specific Aim2 Determine whether administration of mycophenolate mofetil MMF diminishes the rate of progressive decline in GFR and the frequency of ESRD in pediatric patients with a glomerular filtration rate GFR 50 mlminm2 due to congenital uropathies
RESEARCH DESIGN AND METHODS Clinical Definitions CRF GFR 50 mlmin173 m2
Congenital uropathy One of the following categories of kidney disease
1 Dysplasiahypoplasia
2 Congenital obstructive uropathy This category will include children born with structural abnormalities that are associated with renal parenchymal damage eg Prune-Belly syndrome posterior urethral valves myelomeningocele
3 Reflux nephropathy
4 Hereditary non-immunological tubular disorders
The threshold for CRF has been selected to enable recruitment of a sufficient number of patients into this pilot study in a timely fashion In addition at this stage in the disease course renal function can be expected to decline during a relatively short follow-up period Patients with this degree of CRF have nearly a 40 chance of requiring dialysis or a transplant within 2 years This will increase the possibility of demonstrating a therapeutic benefit secondary to treatment with MMF The diagnosis of the congenital urological disease will be established based upon appropriate use of radiological imaging tests and if necessary surgical procedures
Inclusion criteria
1 Age 3-16 years
2 Congenital uropathy
3 Presence of CRF
The lower age limit will enable enrollment of children who are reasonably cooperative are able to take a liquid MMF preparation orally twice a day and in whom an iothalamate clearance can be performed without requiring bladder catheterization The upper limit on age will enable all of the subjects to complete the 2-year study protocol prior to 18 years of age the standard cut-off for enrollment into pediatric clinical trials
Exclusion criteria
1 Diagnosed primary hepatic hematological or immunological disease such as HIV infection that may increase the potential risks of MMF
2 Known sensitivity to MMF
3 Glomerular disease defined on clinical or histopathological grounds
The rate of decline in estimated GFR during the 6 months prior to entry into the study will be recorded in all patients However this value will not serve as an exclusion criterion Even patients with evidence of rapid decline in GFR ie 25 in the previous 6 months will be eligible Such a rapid deterioration is unlikely to occur in the children with congenital uropathy who are enrolled in this pilot study based on the natural history of this form of kidney disease
Sample Population It is anticipated that 12 patients will be enrolled at approximately 4 centers in this multicenter open-label pilot study of MMF in children with CRF due to congenital uropathies
Proposed Intervention with MMF All patients will be treated with MMF in this open-label pilot study Study Phases
There will be two phases in this open-label pilot study
1 RUN-IN 2 months Informed consent will be obtained from parents of eligible patients before beginning this phase of the study Assent will be obtained according to IRB regulations at each participating center
During the 2-month Run-In period eligible patients will be taken off all medications that are contraindicated by the protocol see below Adjunctive Treatments At the discretion of the attending pediatric nephrologist children may be placed on an ACE inhibitor drug The dose must be stabilized 4 weeks prior to the onset of the Treatment Period
2 TREATMENT 24 months GFR will be measured by iothalamate clearance at the start of and at the end of the 12-month Treatment Period Patients whose estimated GFR is 50 mlmin173 M2 during the Run-in Period will be included regardless of the GFR determination using the iothalamate clearance at the beginning of the Treatment Period This will reflect the prevailing clinical practice in which GFR is routinely determined using formula estimates rather than more precise clearance methods HIV testing will be done at the first visit of the Treatment Period and MMF treatment will not be commenced until the HIV-negative status of each eligible patient is confirmed
MMF Dosing The target therapeutic dosage of MMF will be 600 mgm2 body surface areadose maximum dose 1 g given orally twice a day MMF will be started at 200 mgm2 BID and increased at biweekly intervals The full treatment dose 600 mgm2 BID will be achieved at 4 weeks
Safety parameters The dose will be adjusted downward by 200 mgm2BID if a child develops gastrointestinal complaints anemia hematocrit 25 or an absolute neutrophil count ANC 1000-1500 If after 1 week GI toxicity continues or any of the laboratory studies remain abnormal the dose will be further reduced in decrements of 200 mgm2BID If any of these problems persist subsequently the drug will be stopped In a case of severe toxicity more rapid reduction of MMF is allowed at the attending pediatric nephrologists discretion If ANC is less than 1000 the drug will be stopped The need to discontinue MMF treatment in more than 20 of the study patients will be considered an unacceptable high frequency of MMF intolerance in this pilot trial
Adjunctive treatments The use of ACE inhibitors will not be contraindicated in patients who are enrolled in this study However these agents must be started prior to enrollment into the trial and the initial dose will not be increased during the remainder of the 2-year study protocol Administration of recombinant human growth hormone to children who enroll in this pilot study will be permitted if the attending pediatric nephrologist has already prescribed it In addition patients may receive erythropoietin to treat anemia and to prevent the need for red blood cell transfusions
Supplemental doses of antioxidants such as vitamin E will be contraindicated for study participants In addition patients in this trial will not be give any other immunosuppressive therapy All other treatments will be left to the discretion of the attending pediatric nephrologist
Clinical Assessment
Pre-enrollment interval and final visits
CLINICAL BP urine proteincreatinine ratio Uprc microalbuminuria Ualbcr iothalamate clearance IMMUNOLOGICAL HIV testing at the initial visit NUTRITION Counseling to provide RDA for protein and 125 RDA for calories
All serum and urine samples will be stored at -70 degrees C after analysis for future testing if new clinical research findings indicate the value of performing a novel assay to assess disease progression in children with congenital uropathies
Frequency of interval assessment Run-in Period Monthly x 2 Treatment Period Monthly x 3 Then every 3 months for duration of study
Primary Endpoints
1 Safety of MMF in children with congenital uropathies
2 Frequency of ESRD in children with congenital uropathies
Anticipated findings It is predicted that MMF will be well tolerated by at least 80 10 out of 12 of the children with a congenital uropathy and a GFR 50 mlmin173m2 It is also anticipated that MMF will reduce the incidence of ESRD by 50 and thus at most 2 out of 12 patients treated with MMF in this protocol will require dialysis or transplant
Timeline of pilot study It is anticipated that it will take 3 months to set up an Administrative Center at Schneider Children Hospital design Clinical Reporting Forms and create a database at a Data Coordinating Center Patients would be recruited over the next 3 months In order to complete a 2-year Treatment Period the entire study would last for 3½ years
MMF is a well-tolerated safe and effective immunosuppressive medication in adult and pediatric recipients of cadaveric and living-related renal transplants
HYPOTHESIS AND SPECIFIC AIMS This open-label pilot study is designed to test the hypothesis that there is sustained activation of immunoeffector systems that mediate progressive loss of renal function in children with congenital uropathies Immunosuppressive therapy can inhibit this process and retard the rate of decline in kidney function in pediatric patients with structural non-immunological kidney conditions
Specific Aim1 Determine whether administration of mycophenolate mofetil MMF to pediatric patients with a glomerular filtration rate GFR 50 mlminm2 due to congenital uropathies such as dysplasiahypoplasia obstructive uropathy and reflux nephropathy is safe and well tolerated
Specific Aim2 Determine whether administration of mycophenolate mofetil MMF diminishes the rate of progressive decline in GFR and the frequency of ESRD in pediatric patients with a glomerular filtration rate GFR 50 mlminm2 due to congenital uropathies
RESEARCH DESIGN AND METHODS Clinical Definitions CRF GFR 50 mlmin173 m2
Congenital uropathy One of the following categories of kidney disease
1 Dysplasiahypoplasia
2 Congenital obstructive uropathy This category will include children born with structural abnormalities that are associated with renal parenchymal damage eg Prune-Belly syndrome posterior urethral valves myelomeningocele
3 Reflux nephropathy
4 Hereditary non-immunological tubular disorders
The threshold for CRF has been selected to enable recruitment of a sufficient number of patients into this pilot study in a timely fashion In addition at this stage in the disease course renal function can be expected to decline during a relatively short follow-up period Patients with this degree of CRF have nearly a 40 chance of requiring dialysis or a transplant within 2 years This will increase the possibility of demonstrating a therapeutic benefit secondary to treatment with MMF The diagnosis of the congenital urological disease will be established based upon appropriate use of radiological imaging tests and if necessary surgical procedures
Inclusion criteria
1 Age 3-16 years
2 Congenital uropathy
3 Presence of CRF
The lower age limit will enable enrollment of children who are reasonably cooperative are able to take a liquid MMF preparation orally twice a day and in whom an iothalamate clearance can be performed without requiring bladder catheterization The upper limit on age will enable all of the subjects to complete the 2-year study protocol prior to 18 years of age the standard cut-off for enrollment into pediatric clinical trials
Exclusion criteria
1 Diagnosed primary hepatic hematological or immunological disease such as HIV infection that may increase the potential risks of MMF
2 Known sensitivity to MMF
3 Glomerular disease defined on clinical or histopathological grounds
The rate of decline in estimated GFR during the 6 months prior to entry into the study will be recorded in all patients However this value will not serve as an exclusion criterion Even patients with evidence of rapid decline in GFR ie 25 in the previous 6 months will be eligible Such a rapid deterioration is unlikely to occur in the children with congenital uropathy who are enrolled in this pilot study based on the natural history of this form of kidney disease
Sample Population It is anticipated that 12 patients will be enrolled at approximately 4 centers in this multicenter open-label pilot study of MMF in children with CRF due to congenital uropathies
Proposed Intervention with MMF All patients will be treated with MMF in this open-label pilot study Study Phases
There will be two phases in this open-label pilot study
1 RUN-IN 2 months Informed consent will be obtained from parents of eligible patients before beginning this phase of the study Assent will be obtained according to IRB regulations at each participating center
During the 2-month Run-In period eligible patients will be taken off all medications that are contraindicated by the protocol see below Adjunctive Treatments At the discretion of the attending pediatric nephrologist children may be placed on an ACE inhibitor drug The dose must be stabilized 4 weeks prior to the onset of the Treatment Period
2 TREATMENT 24 months GFR will be measured by iothalamate clearance at the start of and at the end of the 12-month Treatment Period Patients whose estimated GFR is 50 mlmin173 M2 during the Run-in Period will be included regardless of the GFR determination using the iothalamate clearance at the beginning of the Treatment Period This will reflect the prevailing clinical practice in which GFR is routinely determined using formula estimates rather than more precise clearance methods HIV testing will be done at the first visit of the Treatment Period and MMF treatment will not be commenced until the HIV-negative status of each eligible patient is confirmed
MMF Dosing The target therapeutic dosage of MMF will be 600 mgm2 body surface areadose maximum dose 1 g given orally twice a day MMF will be started at 200 mgm2 BID and increased at biweekly intervals The full treatment dose 600 mgm2 BID will be achieved at 4 weeks
Safety parameters The dose will be adjusted downward by 200 mgm2BID if a child develops gastrointestinal complaints anemia hematocrit 25 or an absolute neutrophil count ANC 1000-1500 If after 1 week GI toxicity continues or any of the laboratory studies remain abnormal the dose will be further reduced in decrements of 200 mgm2BID If any of these problems persist subsequently the drug will be stopped In a case of severe toxicity more rapid reduction of MMF is allowed at the attending pediatric nephrologists discretion If ANC is less than 1000 the drug will be stopped The need to discontinue MMF treatment in more than 20 of the study patients will be considered an unacceptable high frequency of MMF intolerance in this pilot trial
Adjunctive treatments The use of ACE inhibitors will not be contraindicated in patients who are enrolled in this study However these agents must be started prior to enrollment into the trial and the initial dose will not be increased during the remainder of the 2-year study protocol Administration of recombinant human growth hormone to children who enroll in this pilot study will be permitted if the attending pediatric nephrologist has already prescribed it In addition patients may receive erythropoietin to treat anemia and to prevent the need for red blood cell transfusions
Supplemental doses of antioxidants such as vitamin E will be contraindicated for study participants In addition patients in this trial will not be give any other immunosuppressive therapy All other treatments will be left to the discretion of the attending pediatric nephrologist
Clinical Assessment
Pre-enrollment interval and final visits
CLINICAL BP urine proteincreatinine ratio Uprc microalbuminuria Ualbcr iothalamate clearance IMMUNOLOGICAL HIV testing at the initial visit NUTRITION Counseling to provide RDA for protein and 125 RDA for calories
All serum and urine samples will be stored at -70 degrees C after analysis for future testing if new clinical research findings indicate the value of performing a novel assay to assess disease progression in children with congenital uropathies
Frequency of interval assessment Run-in Period Monthly x 2 Treatment Period Monthly x 3 Then every 3 months for duration of study
Primary Endpoints
1 Safety of MMF in children with congenital uropathies
2 Frequency of ESRD in children with congenital uropathies
Anticipated findings It is predicted that MMF will be well tolerated by at least 80 10 out of 12 of the children with a congenital uropathy and a GFR 50 mlmin173m2 It is also anticipated that MMF will reduce the incidence of ESRD by 50 and thus at most 2 out of 12 patients treated with MMF in this protocol will require dialysis or transplant
Timeline of pilot study It is anticipated that it will take 3 months to set up an Administrative Center at Schneider Children Hospital design Clinical Reporting Forms and create a database at a Data Coordinating Center Patients would be recruited over the next 3 months In order to complete a 2-year Treatment Period the entire study would last for 3½ years
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| CEL214 | None | None | None |