Clinical trial NCT00498368: Rituximab in Progressive Immunoglobulin A (IgA) Nephropathy
Official title: A Multicenter, Randomized, Prospective, Open-Label Trial of Rituximab in the Treatment of Progressive IgA Nephropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: IgA Nephropathy
Keywords: Estimated glomerular filtration rate (GFR)
Proteinuria
Renal Fibrosis
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: Ohio State University
name: Stanford University
name: University of North Carolina, Chapel Hill
name: Columbia University
name: Genentech, Inc.
name: Biogen
First posted: 2007-07-10
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Proteinuria at 12 Months
timeFrame: 1 year
Secondary outcomes:
measure: Biochemical Marker IgA at 12 Months
timeFrame: 12 months
measure: Biochemical Marker Gd-Immunoglobulin A Subclass 1 (IgA1) at 12 Months
timeFrame: 12 months
measure: Biochemical Marker Immunoglobulin G (IgG) AutoAb at 12 Months
timeFrame: 12 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Stanford University
state: California
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina, Chapel Hill
state: North Carolina
city: Columbus
country: United States
facility: The University of Ohio
state: Ohio
Study officials:
affiliation: Mayo Clinic
name: Fernando C. Fervenza, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lafayette RA, Canetta PA, Rovin BH, Appel GB, Novak J, Nath KA, Sethi S, Tumlin JA, Mehta K, Hogan M, Erickson S, Julian BA, Leung N, Enders FT, Brown R, Knoppova B, Hall S, Fervenza FC. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction. J Am Soc Nephrol. 2017 Apr;28(4):1306-1313. doi: 10.1681/ASN.2016060640. Epub 2016 Nov 7.
citation: Yeo SC, Liew A, Barratt J. Emerging therapies in immunoglobulin A nephropathy. Nephrology (Carlton). 2015 Nov;20(11):788-800. doi: 10.1111/nep.12527.