Rituximab in Progressive Immunoglobulin A (IgA) Nephropathy

Study Overview
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Brief Summary
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This study was about IgA nephropathy, a form of kidney disease characterized by the presence of blood and protein in the urine. This study was done to determine if the medication rituximab could reduce protein in the patient's urine. Hypothesis: In patients with progressive IgA nephropathy an intravenous infusion of 1000 mg of rituximab on Day 1 and Day 15 and Days 168 and 182 is superior to conventional therapy in reducing 24 hour proteinuria, and slowing progression of chronic kidney disease.

Detailed Description
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Recent clinical success in the use of Rituximab in the treatment of Lupus nephritis and other forms immune complex glomerulonephritis has led to its investigation in the treatment of IgA nephropathy. Because IgA class antibodies have comparatively short half-lives and that deposition of polymeric forms of IgA contributes to glomerular injury, the researchers speculated that the reduction of circulating IgA could reduce proteinuria and injury in patients with IgA nephropathy. Treatment and Follow-up: Subjects were randomly assigned to receive rituximab or to continue standard care. Both arms received a Omega-3 Fatty Acid Fish Oil Supplement and angiotensin converting enzyme (ACE) inhibitors and/or Angiotensin II receptor blockers (ARBs). ACE inhibitors and/or ARBs were used to achieve a blood pressure goal of <130/80 mmHg. The study was an open-label trial; those assigned to rituximab received a 1 g infusion of rituximab followed by an identical dose 2 weeks later. Premedication with corticosteroids (10 mg dexamethasone intravenously) was also given 30 min prior to the first infusion of each series of rituximab. They received an identical 2 g course of rituximab 6 months later. Subjects were assessed at least every 3 months or as needed for clinical events. This assessment included physical examination, a questionnaire for adverse events, and measurement of routine hematology, serum chemistry, timed urine protein excretion, and for those assigned to rituximab, B-cell subsets. Follow-up was considered complete at 12 months.

Official Title
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A Multicenter, Randomized, Prospective, Open-Label Trial of Rituximab in the Treatment of Progressive IgA Nephropathy

Conditions
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IgA Nephropathy

Intervention / Treatment
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* Drug: Intravenous Rituximab
* Drug: ACE/ARB
* Dietary Supplement: Omega-3 Fatty Acid Fish Oil Supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient between the age of 18 and 70 years of age and able to give informed consent GFR by Cockcroft-Gault or MDRD equations <90 mls/min and >30 mls/min Greater than or equal to 1000 mg of proteinuria/24 hours while on stable ACEi, ARB or renin inhibitor therapy for 2 months. Patients receiving combination ACE or ARB or ACEi and a renin inhibitor for 2 months will only require 500mg/24 hours Blood pressure <130/80 mmHg. The presence of hypertension is not required for study entry, but any patient requiring long term hypertensive medications must have blood pressure controlled <130-80 mmHg, to be considered eligible for the study Female patients with IgA will be considered eligible for study entry if they have a negative urine or serum pregnancy test at the time of screening are agreeable to 2 years of contraception Biopsy proven IgA nephropathy and clinical features consistent with Henoch Schonlein Purpura will be considered eligible for the study Able to swallow the oral medications Exclusion Criteria Clinical and histologic evidence of IgA predominant Lupus nephritis Clinical and histologic evidence of idiopathic IgA forms of membranoproliferative glomerulonephritis Clinical evidence of cirrhosis, chronic active liver disease or known infection with hepatitis B, C or HIV Estimated GFR <30 ml/min/1.73m² at the time of screening Greater than 50% glomerular senescence or cortical scarring on renal biopsy Active systemic infection or history of serious infection within one month of entry History of Crohn's disease or Celiac Sprue Positive pregnancy test or breast feeding at time of study entry or unwilling to comply with contraceptive measures Current or recent (within 30 days) exposure to any investigational drug Serum Cr >3.5 mg/dl or Modification of Diet in Renal Disease (MDRD) calculated GFR <30 mls/min Patients receiving >6 months therapy with oral prednisone or glucocorticoid equivalent Live vaccine within 28 days of study enrollment. General Safety & Laboratory Exclusion Criteria Patients with anaphylaxis and/or known allergic reactions to Rituximab Hemoglobin: <8.5 gm/dL Platelets: <100,000/mm Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 x Upper Limit of Normal unless related to primary disease. Previous Treatment with Rituximab(MabThera®/Rituxan®) Previous treatment with Natalizumab(Tysabri®) History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies History of recurrent significant infection or recurrent bacterial infections Known active bacterial, viral fungal mycobacterial or atypical mycobacterial infections, but excluding fungal infections of nail beds Any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening Ongoing use of high dose steroids(>10 mg/day)or unstable steroid dose in the past 4 weeks Lack of peripheral venous access History of drug, alcohol, or chemical abuse within 6 months prior to screening Pregnancy (a negative serum or urine pregnancy test will be performed for all women of childbearing potential no later than 7 days prior to treatment) or lactation Concomitant or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix History of psychiatric disorder that would interfere with normal participation in this protocol Significant cardiac or pulmonary disease (including obstructive pulmonary disease) Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication Inability to comply with study and follow-up procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab Plus ACE/ARB<br>Intravenous Rituximab therapy, ACE/ARB combination therapy, and Omega-3 Fatty Acid Fish Oil Supplement | Drug: Intravenous Rituximab<br>* Rituximab Therapy [27 Patients] Rituximab 1 gm IV on Treatment Day 1 Rituximab 1 gm IV on Treatment Day 15 Rituximab 1 gm IV on Treatment Day 168 Rituximab 1 gm IV on Treatment Day 182<br>* Other names: Rituxan;Drug: ACE/ARB<br>* ACE inhibitors and /or ARBs will be used to achieve a blood pressure goal of <130/80 millimeters of mercury (mmHg). Patients not attaining the target blood pressure with an ACE inhibitor or ARB alone should be treated with the combination of ACE inhibitor (ACEi) + ARB<br>* Other names: Angiotensin II blockade;Dietary Supplement: Omega-3 Fatty Acid Fish Oil Supplement<br>* Omega-3 Fatty Acid Fish Oil Supplement 3.6 gm eicosapentaenoic acid (EPA)/day<br>|
| Active Comparator: ACE/ARB<br>ACE/ARB therapy and Omega-3 Fatty Acid Fish Oil Supplement | Drug: ACE/ARB<br>* ACE inhibitors and /or ARBs will be used to achieve a blood pressure goal of <130/80 millimeters of mercury (mmHg). Patients not attaining the target blood pressure with an ACE inhibitor or ARB alone should be treated with the combination of ACE inhibitor (ACEi) + ARB<br>* Other names: Angiotensin II blockade;Dietary Supplement: Omega-3 Fatty Acid Fish Oil Supplement<br>* Omega-3 Fatty Acid Fish Oil Supplement 3.6 gm eicosapentaenoic acid (EPA)/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Proteinuria at 12 Months |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Marker IgA at 12 Months |  | 12 months | 
| Biochemical Marker Gd-Immunoglobulin A Subclass 1 (IgA1) at 12 Months |  | 12 months | 
| Biochemical Marker Immunoglobulin G (IgG) AutoAb at 12 Months |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estimated glomerular filtration rate (GFR), Proteinuria, Renal Fibrosis