Rituximab Treatment of Focal Segmental Glomerulosclerosis
Primary Purpose
Focal Segmental Glomerulosclerosis (FSGS)
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
rituximab
Sponsored by
About this trial
This is an interventional treatment trial for Focal Segmental Glomerulosclerosis (FSGS) focused on measuring Focal segmental glomerulosclerosis, FSGS, Proteinuria, rituximab, B cell, autoimmune, CD20, treatment, children
Eligibility Criteria
Inclusion Criteria:
- Primary FSGS involving either native kidneys or primary FSGS recurring after renal transplantation. Age 5-60 years at onset of signs or symptoms of FSGS
- Estimated GFR ≥ 40 ml/min/1.73 m2
- Up/c > 1.0 g protein/g creatinine on first am void
- Biopsy confirmed as primary FSGS (including all subtypes). At least 1 glomerulus demonstrating segmental sclerosis or minimal change FSGS or idiopathic mesangial proliferation with negative immunostains by light microscopy and no dense deposits on electron microscopy. Biopsy required but can be normal for those subjects with rapid recurrence of post transplant FSGS.
- Steroid resistance as defined by primary physician
- If participant is female with reproductive potential, she must be willing to avoid pregnancy and have a negative pregnancy test
- At least one month from last immunization received
Exclusion Criteria:
- Are immunodeficient or have clinically significant chronic lymphopenia
- Have an active infection or positive PPD test result
- Be currently pregnant or lactating, or anticipate getting pregnant
- Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C infection
- Have any complicating medical issues that interfere with study conduct or cause increased risk
- Have a history of malignancies within the last five years except for adequately treated skin cancer
- Have severe cardiac problems such as angina or medically treated arrythmia
Sites / Locations
- Indiana University
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Rituximab
Arm Description
Rituximab (375 mg/m2) will be administered intravenously as per current package label in a facility capable of handling infusion reactions. Subjects would be pre dosed with diphenhydramine and acetaminophen. Solu-Medrol, 1.5 mg/kg would be dosed 1 hour prior to the first dose of rituximab. Three subsequent doses of rituximab will be given at weekly intervals.
Outcomes
Primary Outcome Measures
The primary endpoint will be resolution of proteinuria defined as a Up/C ratio of <0.2.
Secondary Outcome Measures
Number of subjects who achieve partial remission defined at a fall of 50% or more in the Up/C ratio from the pre-treatment baseline
Number of subjects who develop a recurrence or increase of proteinuria on samples obtained at least 4 weeks apart
Effect of treatment on PF levels
Safety as measured by infections and drug infusion reactions.
Full Information
NCT ID
NCT00550342
First Posted
October 26, 2007
Last Updated
September 12, 2017
Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
Genentech, Inc., Indiana University
1. Study Identification
Unique Protocol Identification Number
NCT00550342
Brief Title
Rituximab Treatment of Focal Segmental Glomerulosclerosis
Official Title
Anti-CD20, Rituximab, for the Treatment of Recurrent or Primary Resistant Focal Segmental Glomerulosclerosis (FSGS)
Study Type
Interventional
2. Study Status
Record Verification Date
April 2012
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
December 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
Genentech, Inc., Indiana University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to determine whether the approved drug, rituximab, is effective in the treatment of focal segmental glomerulosclerosis (FSGS)
Detailed Description
Focal segmental glomerulosclerosis (FSGS) remains an enigmatic disease despite many years of study. There has been a recent increased incidence of FSGS particularly in African Americans in whom the outcome tends to be worse. In about 30% of patients transplanted for FSGS, the disease recurs and often results in severe nephrotic syndrome and accelerated graft loss. FSGS is a common cause of nephrotic disease accounting for 10-20% of cases of idiopathic nephrotic syndrome in children and 35% of cases in adults. Most cases are refractory to current therapy resulting in the ultimate progression to end stage renal disease. Overall, FSGS accounts for about 15% of pediatric and 5% of adult cases of end stage renal disease. With the frequent post transplant recurrence, the morbidity and mortality of FSGS is increased. Thus, FSGS is a disease that is associated with a large cost to society and long-term morbidity to the individual patient. A treatment that could induce permanent remission and reverse organ damage would make a major contribution to society by reduction of these expenses. A circulating Permeability Factor (PF, Savin Factor) has been suspected as central to the pathogenesis of recurrent disease but its identity has been difficult to discern. The molecular weight has reported to be between 30 and 100 kDa. Although, PF has been reported to adhere to protein A columns and such columns can be part of the treatment of FSGS, this molecular weight would exclude PF being an intact antibody. Immunosuppressive agents have been the only therapy demonstrating efficacy, albeit partial, suggesting that at least some cases of FSGS are immune mediated. While high dose steroids are the first line of treatment for FSGS, cyclosporine has been efficacious in randomized trials and has been used for steroid resistant FSGS but is associated with substantial toxicity. If cyclosporine fails, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and most recently mycophenolate mofetil (MMF) have been used with variable efficacy.
Rituximab, primarily indicated for treatment of lymphoma, has become a first line agent in the treatment of post transplant lymphoma. However, it has been used with increased frequency to treat various autoimmune diseases including those such as rheumatoid arthritis that have been thought to be primarily T-cell mediated and others such as immune thrombocytopenia purpura that have been thought to be primarily B-cell mediated. In a trial being conducted by the Immune Tolerance Network, ANCA positive vasculitis is being treated with rituximab and it appears that a short course of rituximab leads to tolerance in this autoimmune disease. Rituximab's mechanism of action in the various autoimmune diseases for which has efficacy has been variously suggested to result from elimination of either circulating autoantibody, by elimination of B-cell produced cytokines, or by interference with the antigen presentation provide by B cells.
We have recently had a case of immediate post transplant recurrence of FSGS in a child that failed to respond to MMF, steroids, long-term plasmapheresis and conversion from tacrolimus to cyclosporine. The FSGS associated proteinuria however completely resolved at about 6 months after treatment of post transplant lymphoma with 6 doses of rituximab. A similar case that also resolved after treatment of PTLD with rituximab was recently reported. While the mechanism of action of both cyclosporine and MMF is unknown in FSGS, both drugs have been shown to have activity against B cells. The response seen in these two recent cases following treatment with a B cell specific agent leads to the hypothesis that at least some cases of FSGS have an autoimmune mechanism in which B cells play a central role. We propose to test this hypothesis by the treatment of patients with recurrent or primary persistent FSGS with rituximab.
This study will be a single center, single-arm, pilot trial. As the study will be registered at clintrials.gov, subjects may be referred from outside physicians. However, all treatment will be done at IU in the GCRC. After meeting inclusion/exclusion criteria and signing the consent, serum for PF levels, and blood for B cell flow cytometry will be obtained. Rituximab (375 mg/m2) will be administered intravenously as per current package label in a facility capable of handling infusion reactions. Subjects would be pre dosed with diphenhydramine and acetaminophen. Solu-Medrol, 1.5 mg/kg would be dosed 1 hour prior to the first dose of rituximab. Three subsequent doses of rituximab will be given at weekly intervals. Study visits will then be conducted monthly thereafter for the 6 months and then every 3 months, at which time, assessments of safety will be made. Efficacy will be determined by monitoring first AM Uprotein/C ratio. Flow cytometry, PF factor, urine proteomics and general blood work including CBC, Chemistry, electrolytes, serum immunoglobulin will also be done. During the second year, subjects would be followed every three months. The primary endpoint will be resolution of proteinuria defined as a Up/C ratio of <0.2. Secondary endpoints will be the number of subjects who achieve partial remission defined at a fall of 50% or more in the Up/C ratio from the pre-treatment baseline; the number of patients who develop a recurrence or increase of proteinuria on samples obtained at least 4 weeks apart; effect of treatment on PF levels; safety as measured by infections and drug infusion reactions. Consideration will be given to a plan of redosing in subjects who relapse after initial response.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Focal Segmental Glomerulosclerosis (FSGS)
Keywords
Focal segmental glomerulosclerosis, FSGS, Proteinuria, rituximab, B cell, autoimmune, CD20, treatment, children
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Rituximab
Arm Type
Experimental
Arm Description
Rituximab (375 mg/m2) will be administered intravenously as per current package label in a facility capable of handling infusion reactions. Subjects would be pre dosed with diphenhydramine and acetaminophen. Solu-Medrol, 1.5 mg/kg would be dosed 1 hour prior to the first dose of rituximab. Three subsequent doses of rituximab will be given at weekly intervals.
Intervention Type
Drug
Intervention Name(s)
rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
375 mg/m2 intravenously for 4 doses
Primary Outcome Measure Information:
Title
The primary endpoint will be resolution of proteinuria defined as a Up/C ratio of <0.2.
Time Frame
One year
Secondary Outcome Measure Information:
Title
Number of subjects who achieve partial remission defined at a fall of 50% or more in the Up/C ratio from the pre-treatment baseline
Time Frame
one year
Title
Number of subjects who develop a recurrence or increase of proteinuria on samples obtained at least 4 weeks apart
Time Frame
one year
Title
Effect of treatment on PF levels
Time Frame
one year
Title
Safety as measured by infections and drug infusion reactions.
Time Frame
one year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Primary FSGS involving either native kidneys or primary FSGS recurring after renal transplantation. Age 5-60 years at onset of signs or symptoms of FSGS
Estimated GFR ≥ 40 ml/min/1.73 m2
Up/c > 1.0 g protein/g creatinine on first am void
Biopsy confirmed as primary FSGS (including all subtypes). At least 1 glomerulus demonstrating segmental sclerosis or minimal change FSGS or idiopathic mesangial proliferation with negative immunostains by light microscopy and no dense deposits on electron microscopy. Biopsy required but can be normal for those subjects with rapid recurrence of post transplant FSGS.
Steroid resistance as defined by primary physician
If participant is female with reproductive potential, she must be willing to avoid pregnancy and have a negative pregnancy test
At least one month from last immunization received
Exclusion Criteria:
Are immunodeficient or have clinically significant chronic lymphopenia
Have an active infection or positive PPD test result
Be currently pregnant or lactating, or anticipate getting pregnant
Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C infection
Have any complicating medical issues that interfere with study conduct or cause increased risk
Have a history of malignancies within the last five years except for adequately treated skin cancer
Have severe cardiac problems such as angina or medically treated arrythmia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark D Pescovitz, MD
Organizational Affiliation
Indiana University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
16672715
Citation
Pescovitz MD, Book BK, Sidner RA. Resolution of recurrent focal segmental glomerulosclerosis proteinuria after rituximab treatment. N Engl J Med. 2006 May 4;354(18):1961-3. doi: 10.1056/NEJMc055495. No abstract available.
Results Reference
background
Learn more about this trial
Rituximab Treatment of Focal Segmental Glomerulosclerosis
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