Focal Segmental Glomerulosclerosis Clinical Trial (FSGS-CT)
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|ClinicalTrials.gov Identifier: NCT00135811|
Recruitment Status : Completed
First Posted : August 26, 2005
Last Update Posted : May 22, 2012
|First Submitted Date ICMJE||August 24, 2005|
|First Posted Date ICMJE||August 26, 2005|
|Last Update Posted Date||May 22, 2012|
|Study Start Date ICMJE||November 2004|
|Actual Primary Completion Date||October 2009 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The primary outcome is a 6-level ordinal variable defined based on the achievement of remission from proteinuria during the first 52 weeks after randomization. [ Time Frame: first 52 weeks after randomization. ]|
|Original Primary Outcome Measures ICMJE
||The primary outcome is a 6-level ordinal variable defined based on the achievement of remission from proteinuria during the first 52 weeks after randomization.|
|Change History||Complete list of historical versions of study NCT00135811 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||The main secondary outcome is a 5-level ordinal variable defined based on the persistence of remissions after immunosuppressive agents are withdrawn. [ Time Frame: based on the participant's level of proteinuria during the period from week 52 through week 78 following withdrawal of CSA or MMF/Pulse steroids ]|
|Original Secondary Outcome Measures ICMJE
||To main secondary outcome is a 5-level ordinal variable defined based on the persistence of remissions after immunosuppressive agents are withdrawn.|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Focal Segmental Glomerulosclerosis Clinical Trial (FSGS-CT)|
|Official Title ICMJE||Focal Segmental Glomerulosclerosis Clinical Trial|
|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.|
Background/Rationale. 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. MMF/Pulse Steroids. The treatment regimens in both arms also include angiotensin converting enzyme inhibitor (ACEI) therapy and alternate day low dose prednisone. The CSA and MMF/Pulse 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 MMF/Pulse 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 MMF/Pulse 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.
CSA: The initial target dose for CSA is 5 - 6 mg/kg per day divided into two daily doses. Dosage is subsequently adjusted to maintain a 12-hour trough CSA blood concentration of 100 - 250 ng/ml. CSA is maintained for 12 months following randomization.
MMF/Pulse Steroid Arm:
MMF: The target dose for MMF is 25-36 mg/kg per day with a maximum dose of 2 g/day divided into two daily doses, maintained for 12 months following randomization.
Dexamethasone: The target dose for dexamethasone is 0.9 mg/kg 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 0.4 mg/kg to 0.6 mg/kg depending on the patient's 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 0.3 mg/kg 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:
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 Up/c, 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 Up/c, basic blood chemistries (BUN, creatinine, serum electrolytes and glucose) and hematology in the MMF/Pulse 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 Up/c from the mean of two baseline measurements to a level between 0.2 and 1.0. A complete remission is defined as a decline in Up/c to a level no greater than 0.2.
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 Up/c 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 Up/c > 0.2 after week 26 but before week 52. Level 1 is assigned if the participant achieves a complete remission at week 52 and has had Up/c < 0.2 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 MMF/Pulse 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 10.8% and 11.5% between the MMF/Pulse Steroid and the CSA groups.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Glomerulosclerosis, Focal|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Estimated Enrollment ICMJE
|Original Enrollment ICMJE
|Actual Study Completion Date||October 2009|
|Actual Primary Completion Date||October 2009 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Note: Participants with conditions meeting exclusion criteria at a particular evaluation for eligibility may be re-evaluated at a later time to determine if the conditions have changed so that all entry criteria are met. In particular, if blood pressure > 140/95 or > 95th percentile for age/height while the participant is on less than three antihypertensive agents, the participant may be re-evaluated for eligibility after adding other antihypertensive agents so long as the total number of agents does not exceed three.
|Ages||2 Years to 40 Years (Child, Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00135811|
|Other Study ID Numbers ICMJE||63490 (completed)|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Marva Moxey-Mims, M.D., NIH Project Officer|
|Study Sponsor ICMJE||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|
|Collaborators ICMJE||The Cleveland Clinic|
|PRS Account||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|
|Verification Date||May 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP