Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00135811
Status:
COMPLETED
Last Update Posted:
2012-05-22
First Post:
2005-08-24
Brief Title:
Focal Segmental Glomerulosclerosis Clinical Trial FSGS-CT
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Study Overview
Official Title:
Focal Segmental Glomerulosclerosis Clinical Trial
Status:
COMPLETED
Status Verified Date:
2012-05
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 FSGS Clinical Trial is a multi-center prospective controlled open label randomized trial designed to determine if treatment with mycophenolate mofetil MMF in conjunction with pulse steroids is superior to treatment with Cyclosporine-A CSA in inducing remission from proteinuria over 12 months
Detailed Description:
BackgroundRationale Primary FSGS is a leading cause of end stage renal disease in both children and adults with complete loss of kidney function in 50 of patients over 10 years Evidence-based treatment guidelines for FSGS have not been developed because of the lack of controlled studies and the small number of patients included in most reports Over the past decade a number of studies have reported therapeutic efficacy for treatment with Cyclosporine-A CSA in patients with nephrotic syndrome including patients with steroid resistant FSGS There have been two controlled trials of treatment with CSA in steroid resistant FSGS one in children and one in adult patients Consequently CSA is the only medication that has been documented to be efficacious in a controlled trial in both children and adults with steroid resistant FSGS The experience with mycophenolate mofetil MMF in the treatment of patients with steroid resistant FSGS has been limited to uncontrolled trials in adult patients and children
Patient Population The patient population consists of children and adults between the ages of 2 and 40 years with steroid resistant FSGS
Study Design The experimental design is a multi-center prospective controlled open label randomized trial comparing two treatment regimens CSA vs MMFPulse Steroids The treatment regimens in both arms also include angiotensin converting enzyme inhibitor ACEI therapy and alternate day low dose prednisone The CSA and MMFPulse steroid treatment regimens will be implemented over the first 26 weeks after randomization and continued to 52 weeks if a response in proteinuria occurs The ACE inhibitor component continues for an additional 26 weeks after withdrawal of initial therapies
Logistical Structure Participants are recruited at over 130 participating sites in North America which are affiliated with one of five Core Coordinating Centers
Primary Objectives The primary objective of the trial is to determine if treatment with MMFPulse steroids is superior to treatment with CSA in inducing remission from proteinuria over 12 months The main secondary objective is to determine if treatment with MMFPulse steroids is superior to treatment with CSA in inducing remissions which persist for at least 6 months following withdrawal of immunosuppressive therapy but while maintaining ACEI or angiotensin receptor blocker ARB therapy
Biorepository Specimens Collection of specimens for biological and DNA repositories will serve as a national resource for ancillary studies investigating the pathogenesis of FSGS
Duration of Therapeutic Regimens and Follow-up The study treatment duration for a randomized patient depends on the level of response to treatment as follows 26 weeks if neither a partial or complete remission occurs at the 26-week visit 52 weeks if there is a partial or complete remission at 26 weeks but not at 52 weeks and 78 weeks if partial or complete remissions are recorded at both the 26- and 52-week visits For all patients low intensity follow-up for long-term assessment of renal function is maintained after termination of the therapeutic regimens until September 2008
Inclusion Criteria
Age 2-40 years at onset of signs or symptoms of FSGS
Age 40 years at randomization
Estimated glomerular filtration rate GFR 40 mlmin173 m2
Urine proteincreatinine Upc 10 on first am void
Biopsy confirmed primary FSGS including all subtypes
Steroid resistance established by failure to achieve a sustained Upc 10 following a steroid treatment course of at least 4 weeks with a minimum cumulative dose of 56 mgkg or 1680 mg of prednisone and
Willingness to follow the clinical trial protocol including medications and baseline and follow-up visits and procedures
Exclusion Criteria
Secondary FSGS
Prior therapy with sirolimus CSA tacrolimus MMF or azathioprin Imuran - - Treated with cytoxan chlorambucil levamisole methotrexate or nitrogen mustard in the last 30 days
Lactation pregnancy or refusal of birth control in women of child bearing potential
Participation in another therapeutic trial concurrently or 30 days prior to randomization
Activeserious infection
Malignancy
Blood pressure 14095 or 95th percentile for ageheight
Use of 4 or more antihypertensive agents for the primary purpose of controlling blood pressure
Previously diagnosed diabetes mellitus type I or II DM I or II
Clinical evidence of cirrhosis or chronic active liver disease
Absolute neutrophil count ANC 2000mm3 or hematocrit HCT 28
History of significant gastrointestinal disorder
Organ transplantation
Obesity based on estimated dry weight at onset of disease prior to steroid therapy defined as body mass index BMI 97th percentile for ages 2-20 years and BMI 40 kgm2 for age 21 years
Allergy to study medications and 17 Inability to consentassent
Therapeutic Regimens
CSA Arm
CSA The initial target dose for CSA is 5 - 6 mgkg per day divided into two daily doses Dosage is subsequently adjusted to maintain a 12-hour trough CSA blood concentration of 100 - 250 ngml CSA is maintained for 12 months following randomization
MMFPulse Steroid Arm
MMF The target dose for MMF is 25-36 mgkg per day with a maximum dose of 2 gday divided into two daily doses maintained for 12 months following randomization
Dexamethasone The target dose for dexamethasone is 09 mgkg per dose with a maximum dose of 40 mg given as a single dose on two consecutive days at the start of weeks 1 2 3 4 5 6 7 8 10 12 14 16 18 20 22 24 26 30 34 38 42 46 and 50 for a total of 46 doses
Both Treatment Arms
ACEI A maximally tolerated dose of the angiotensin converting enzyme inhibitor lisinopril will be attempted in three steps at two-week intervals The target maintenance dose ranges from 04 mgkg to 06 mgkg depending on the patients weight Patients who are unable to tolerate treatment with ACEI or who have been previously intolerant of ACEI will receive the angiotensin receptor blocker ARB losartan The duration for the ACEI or ARB therapy is 18 months
Prednisone Target dose for prednisone is 03 mgkg per dose to a maximum dose of 15 mg administered as single dose every other day for the first 6 months of the 12-month treatment period after randomization
Dose Adjustments for Toxicity
Known toxicities associated with each of the therapeutic agents are delineated in the protocol A stepped dosage reduction protocol is implemented following confirmed toxicities as follows
Step 1 Reduce dosage to 23 of full target dose
Step 2 If the toxicity persists following Step 1 reduce dose to 13 of full target dose
Step 3 If the toxicity persists following Step 2 discontinue medication In certain cases the protocol stipulates that the attempts should be made to reverse the dose reductions following the stepped sequence in reverse order following remission of toxicities
Study Visits and Measurements Main Outcome Assessment Visits The main visits for assessment of study outcomes are conducted at baseline and at weeks 26 52 and 78 of follow-up These visits each include 2 first-morning Upc a full panel of serum and urine biochemistry measurements complete blood count a quality of life assessment SF-36 in adults PedsQL in children a complete physical examination recording of medications and side effects plus additional urine serum plasma specimens for storage in a repository Whole blood for DNA extraction will be collected at onset of therapy and placed in a repository for consenting patients
Other Visits In addition to the main outcome assessment visits at baseline and weeks 26 52 and 78 first morning urine samples for determination of Upc basic blood chemistries BUN creatinine serum electrolytes and glucose and hematology in the MMFPulse Steroids arm are also obtained immediately after randomization and at follow-up weeks 2 4 6 8 14 20 32 38 44 and 65 CSA trough level fasting lipids serum albumin and other blood chemistries are obtained at designated subsets of these visits
Adverse event monitoring Adverse events including all hospitalizations and all modifications to the dosages of the study medications are recorded throughout the follow-up period
Definition of Partial and Complete Remissions At each protocol assessment of proteinuria a partial remission is defined as a 50 or greater decline in the first morning Upc from the mean of two baseline measurements to a level between 02 and 10 A complete remission is defined as a decline in Upc to a level no greater than 02
Primary Outcome The primary outcome is a 6-level ordinal classification based on the achievement of remission during the first 52 weeks after randomization The least favorable outcome designated as level 6 is assigned if no partial or complete remission is achieved between weeks 2 through 26 inclusive Level 5 is assigned if the participant achieves at least one partial or complete remission between weeks 2 and 20 but does not achieve either a partial or complete remission at week 26 By this definition the primary outcome is not affected by the Upc after 26 weeks if a partial or complete remission is not achieved at 26 weeks allowing those participants to switch to alternative therapies without affecting the primary analysis
For participants with a partial or complete remission at week 26 a score between 1 and 4 is assigned depending on the remission status between week 26 and week 52 Level 4 is assigned if the participant fails to achieve either a partial or complete remission at week 52 or has a sustained relapse between weeks 26 and 52 Level 3 is assigned if the participant achieves a partial remission at week 52 Level 2 is assigned if the participant achieves a complete remission at week 52 but has had at least one Upc 02 after week 26 but before week 52 Level 1 is assigned if the participant achieves a complete remission at week 52 and has had Upc 02 since the week 26 visit
Main Secondary Outcome The main secondary outcome is a 5-level ordinal classification which evaluates the extent to which remissions from proteinuria persist during the period from week 52 to week 78 after immunosuppressive therapy is withdrawn but while remaining on ACEI or ARB treatment
Other Outcomes Other outcomes include the change in quality of life the numbers of adverse events and extra-renal complications and preservation of renal function
Sample Size The target sample size is 500 patients
Primary Analysis The primary statistical analysis will compare the six-level primary outcome variable between the randomized treatment groups The six levels will be assigned scores ranging from 1 for the most favorable category to 6 for the least favorable category and the mean response score will be compared between the CSA and MMFPulse steroid groups within each of the four randomization strata defined by baseline estimated GFR and race The analysis will be carried out by intent-to-treat A 2-sided test will be conducted at the 5 significance level
Study Power Depending on the remission rate in the control group classified as levels 1 2 or 3 for the primary outcome the sample size of 500 randomized patients is sufficient to obtain 80 power to detect an absolute increase in remission rate of between 108 and 115 between the MMFPulse Steroid and the CSA groups
Patient Population The patient population consists of children and adults between the ages of 2 and 40 years with steroid resistant FSGS
Study Design The experimental design is a multi-center prospective controlled open label randomized trial comparing two treatment regimens CSA vs MMFPulse Steroids The treatment regimens in both arms also include angiotensin converting enzyme inhibitor ACEI therapy and alternate day low dose prednisone The CSA and MMFPulse steroid treatment regimens will be implemented over the first 26 weeks after randomization and continued to 52 weeks if a response in proteinuria occurs The ACE inhibitor component continues for an additional 26 weeks after withdrawal of initial therapies
Logistical Structure Participants are recruited at over 130 participating sites in North America which are affiliated with one of five Core Coordinating Centers
Primary Objectives The primary objective of the trial is to determine if treatment with MMFPulse steroids is superior to treatment with CSA in inducing remission from proteinuria over 12 months The main secondary objective is to determine if treatment with MMFPulse steroids is superior to treatment with CSA in inducing remissions which persist for at least 6 months following withdrawal of immunosuppressive therapy but while maintaining ACEI or angiotensin receptor blocker ARB therapy
Biorepository Specimens Collection of specimens for biological and DNA repositories will serve as a national resource for ancillary studies investigating the pathogenesis of FSGS
Duration of Therapeutic Regimens and Follow-up The study treatment duration for a randomized patient depends on the level of response to treatment as follows 26 weeks if neither a partial or complete remission occurs at the 26-week visit 52 weeks if there is a partial or complete remission at 26 weeks but not at 52 weeks and 78 weeks if partial or complete remissions are recorded at both the 26- and 52-week visits For all patients low intensity follow-up for long-term assessment of renal function is maintained after termination of the therapeutic regimens until September 2008
Inclusion Criteria
Age 2-40 years at onset of signs or symptoms of FSGS
Age 40 years at randomization
Estimated glomerular filtration rate GFR 40 mlmin173 m2
Urine proteincreatinine Upc 10 on first am void
Biopsy confirmed primary FSGS including all subtypes
Steroid resistance established by failure to achieve a sustained Upc 10 following a steroid treatment course of at least 4 weeks with a minimum cumulative dose of 56 mgkg or 1680 mg of prednisone and
Willingness to follow the clinical trial protocol including medications and baseline and follow-up visits and procedures
Exclusion Criteria
Secondary FSGS
Prior therapy with sirolimus CSA tacrolimus MMF or azathioprin Imuran - - Treated with cytoxan chlorambucil levamisole methotrexate or nitrogen mustard in the last 30 days
Lactation pregnancy or refusal of birth control in women of child bearing potential
Participation in another therapeutic trial concurrently or 30 days prior to randomization
Activeserious infection
Malignancy
Blood pressure 14095 or 95th percentile for ageheight
Use of 4 or more antihypertensive agents for the primary purpose of controlling blood pressure
Previously diagnosed diabetes mellitus type I or II DM I or II
Clinical evidence of cirrhosis or chronic active liver disease
Absolute neutrophil count ANC 2000mm3 or hematocrit HCT 28
History of significant gastrointestinal disorder
Organ transplantation
Obesity based on estimated dry weight at onset of disease prior to steroid therapy defined as body mass index BMI 97th percentile for ages 2-20 years and BMI 40 kgm2 for age 21 years
Allergy to study medications and 17 Inability to consentassent
Therapeutic Regimens
CSA Arm
CSA The initial target dose for CSA is 5 - 6 mgkg per day divided into two daily doses Dosage is subsequently adjusted to maintain a 12-hour trough CSA blood concentration of 100 - 250 ngml CSA is maintained for 12 months following randomization
MMFPulse Steroid Arm
MMF The target dose for MMF is 25-36 mgkg per day with a maximum dose of 2 gday divided into two daily doses maintained for 12 months following randomization
Dexamethasone The target dose for dexamethasone is 09 mgkg per dose with a maximum dose of 40 mg given as a single dose on two consecutive days at the start of weeks 1 2 3 4 5 6 7 8 10 12 14 16 18 20 22 24 26 30 34 38 42 46 and 50 for a total of 46 doses
Both Treatment Arms
ACEI A maximally tolerated dose of the angiotensin converting enzyme inhibitor lisinopril will be attempted in three steps at two-week intervals The target maintenance dose ranges from 04 mgkg to 06 mgkg depending on the patients weight Patients who are unable to tolerate treatment with ACEI or who have been previously intolerant of ACEI will receive the angiotensin receptor blocker ARB losartan The duration for the ACEI or ARB therapy is 18 months
Prednisone Target dose for prednisone is 03 mgkg per dose to a maximum dose of 15 mg administered as single dose every other day for the first 6 months of the 12-month treatment period after randomization
Dose Adjustments for Toxicity
Known toxicities associated with each of the therapeutic agents are delineated in the protocol A stepped dosage reduction protocol is implemented following confirmed toxicities as follows
Step 1 Reduce dosage to 23 of full target dose
Step 2 If the toxicity persists following Step 1 reduce dose to 13 of full target dose
Step 3 If the toxicity persists following Step 2 discontinue medication In certain cases the protocol stipulates that the attempts should be made to reverse the dose reductions following the stepped sequence in reverse order following remission of toxicities
Study Visits and Measurements Main Outcome Assessment Visits The main visits for assessment of study outcomes are conducted at baseline and at weeks 26 52 and 78 of follow-up These visits each include 2 first-morning Upc a full panel of serum and urine biochemistry measurements complete blood count a quality of life assessment SF-36 in adults PedsQL in children a complete physical examination recording of medications and side effects plus additional urine serum plasma specimens for storage in a repository Whole blood for DNA extraction will be collected at onset of therapy and placed in a repository for consenting patients
Other Visits In addition to the main outcome assessment visits at baseline and weeks 26 52 and 78 first morning urine samples for determination of Upc basic blood chemistries BUN creatinine serum electrolytes and glucose and hematology in the MMFPulse Steroids arm are also obtained immediately after randomization and at follow-up weeks 2 4 6 8 14 20 32 38 44 and 65 CSA trough level fasting lipids serum albumin and other blood chemistries are obtained at designated subsets of these visits
Adverse event monitoring Adverse events including all hospitalizations and all modifications to the dosages of the study medications are recorded throughout the follow-up period
Definition of Partial and Complete Remissions At each protocol assessment of proteinuria a partial remission is defined as a 50 or greater decline in the first morning Upc from the mean of two baseline measurements to a level between 02 and 10 A complete remission is defined as a decline in Upc to a level no greater than 02
Primary Outcome The primary outcome is a 6-level ordinal classification based on the achievement of remission during the first 52 weeks after randomization The least favorable outcome designated as level 6 is assigned if no partial or complete remission is achieved between weeks 2 through 26 inclusive Level 5 is assigned if the participant achieves at least one partial or complete remission between weeks 2 and 20 but does not achieve either a partial or complete remission at week 26 By this definition the primary outcome is not affected by the Upc after 26 weeks if a partial or complete remission is not achieved at 26 weeks allowing those participants to switch to alternative therapies without affecting the primary analysis
For participants with a partial or complete remission at week 26 a score between 1 and 4 is assigned depending on the remission status between week 26 and week 52 Level 4 is assigned if the participant fails to achieve either a partial or complete remission at week 52 or has a sustained relapse between weeks 26 and 52 Level 3 is assigned if the participant achieves a partial remission at week 52 Level 2 is assigned if the participant achieves a complete remission at week 52 but has had at least one Upc 02 after week 26 but before week 52 Level 1 is assigned if the participant achieves a complete remission at week 52 and has had Upc 02 since the week 26 visit
Main Secondary Outcome The main secondary outcome is a 5-level ordinal classification which evaluates the extent to which remissions from proteinuria persist during the period from week 52 to week 78 after immunosuppressive therapy is withdrawn but while remaining on ACEI or ARB treatment
Other Outcomes Other outcomes include the change in quality of life the numbers of adverse events and extra-renal complications and preservation of renal function
Sample Size The target sample size is 500 patients
Primary Analysis The primary statistical analysis will compare the six-level primary outcome variable between the randomized treatment groups The six levels will be assigned scores ranging from 1 for the most favorable category to 6 for the least favorable category and the mean response score will be compared between the CSA and MMFPulse steroid groups within each of the four randomization strata defined by baseline estimated GFR and race The analysis will be carried out by intent-to-treat A 2-sided test will be conducted at the 5 significance level
Study Power Depending on the remission rate in the control group classified as levels 1 2 or 3 for the primary outcome the sample size of 500 randomized patients is sufficient to obtain 80 power to detect an absolute increase in remission rate of between 108 and 115 between the MMFPulse Steroid and the CSA groups
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