Rituximab in Progressive Immunoglobulin A (IgA) Nephropathy

Phase 4

Completed

Conditions: IgA Nephropathy

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

Registration Number: NCT00498368

Lead Sponsor: Mayo Clinic

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 34

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rituximab Plus ACE/ARB	Omega-3 Fatty Acid Fish Oil Supplement	Intravenous Rituximab therapy, ACE/ARB combination therapy, and Omega-3 Fatty Acid Fish Oil Supplement
ACE/ARB	Omega-3 Fatty Acid Fish Oil Supplement	ACE/ARB therapy and Omega-3 Fatty Acid Fish Oil Supplement
ACE/ARB	ACE/ARB	ACE/ARB therapy and Omega-3 Fatty Acid Fish Oil Supplement
Rituximab Plus ACE/ARB	Intravenous Rituximab	Intravenous Rituximab therapy, ACE/ARB combination therapy, and Omega-3 Fatty Acid Fish Oil Supplement
Rituximab Plus ACE/ARB	ACE/ARB	Intravenous Rituximab therapy, ACE/ARB combination therapy, and Omega-3 Fatty Acid Fish Oil Supplement

Primary Outcome Measures

Name	Time	Method
Change in Proteinuria at 12 Months	1 year

Secondary Outcome Measures

Name	Time	Method
Biochemical Marker Gd-Immunoglobulin A Subclass 1 (IgA1) at 12 Months	12 months
Biochemical Marker IgA at 12 Months	12 months
Biochemical Marker Immunoglobulin G (IgG) AutoAb at 12 Months	12 months

Trial Locations

Locations (5): Stanford University
🇺🇸
San Francisco, California, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
University of North Carolina, Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
The University of Ohio
🇺🇸
Columbus, Ohio, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States