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Rituximab in Progressive IgA Nephropathy

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Ohio State University
Stanford University
University of North Carolina, Chapel Hill
Columbia University
Information provided by (Responsible Party):
Fernando Fervenza, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00498368
First received: July 9, 2007
Last updated: November 18, 2014
Last verified: November 2014
  Purpose

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, we speculate that the reduction of circulating IgA may reduce proteinuria and injury in patients with IgA nephropathy. Moreover, the absence of prospective trials in the treatment of IgA disease and the lack of consensus for long-term treatment, the superior side-effect profile of this form of therapy may lead to significant advances in the treatment of this prevalent from of glomerulonephritis.


Condition Intervention Phase
IgA Nephropathy
Drug: Intravenous Rituximab
Drug: ACE/ARB
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Prospective, Open-Label Trial of Rituximab in the Treatment of Progressive IgA Nephropathy

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Change in Proteinuria and EGFR at 12 months [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Change in the percentage of obsolete glomeruli senescence and interstitial fibrosis in patients undergoing repeat kidney biopsy after 12 months of therapy [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 54
Study Start Date: February 2009
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1-Rituximab Plus ACE/ARB
Intravenous Rituximab Therapy plus ACE/ARB combination therapy
Drug: Intravenous Rituximab

Group 1: 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 •• An ACE inhibitors and /or ARBs will be used to achieve a B/P goal of <130/80mmHg, plus Omega-3 Fatty Acid Fish Oil Supplements 3.6 gm EPA/day
Other Name: Rituxan
Active Comparator: ACE/ARB
ACE/ARB therapy without the addition of Rituximab
Drug: ACE/ARB
  • An ACE inhibitors and /or ARBs will be used to achieve a B/P goal of <130/80mmHg. Patients not attaining the target blood pressure with an ACE inhibitor or ARB alone should be treated with the combination of ACEi + ARB
  • Omega-3 Fatty Acid Fish Oil Supplements 3.6 gm EPA/day
Other Name: Angiotensin II blockade

Detailed Description:

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. .

2.0 OBJECTIVES

2.1 Primary Efficacy Endpoints:

Percentage of patients in each group achieving complete or partial response as defined below:

Complete Response: At 12 months

  1. < 300 mg proteinuria/24 hours Pediatric Criteria: First morning void urine protein: creatinine ratio <0.3
  2. No greater than a 10% reduction in baseline estimated GFR as determined by MDRD (4 point) formula Partial Response: At 12 months

1) > 50% reduction in 24 hour proteinuria 2) No greater than a 25% reduction in baseline estimated GFR as determined by MDRD formula No Response: At 12 months

  1. A 50% reduction, unchanged or increasing proteinuria over baseline levels will be considered no response
  2. A greater than a 30% reduction in baseline estimated GFR as determined by MDRD formula

2.2 Primary Safety Endpoints:

  • Incidence of Infusion Related Reactions: Defined as the development of hypotension, generalized pruritus, chills/rigors, angioedema and/or bronchospasm.
  • Pulmonary Complications: Defined as a hypoxia, pulmonary infiltrates and/or acute respiratory failure
  • Incidence of Major Infections: Defined as the development of pneumonia, complicated UTI/Pyelonephritis, Sepsis, and Meningitis.
  • Development of Progressive Multifocal Leukoencephalopathy (PML)

2.3 Secondary Exploratory Efficacy Endpoints:

A) For patients in Groups 1 & 2 consenting to a repeat kidney biopsy at 12 months, a secondary endpoint will include the percentage of patients in experiencing a 25% increase in cortical fibrosis. The response rate will be semi-quantified by the change in cortical fibrosis as measured by changes in Sirius Red staining of interstitial collagen. A patient will be considered a complete or partial response or no response according to the following criteria:

Complete: Less than 10% rise in cortical fibrosis as measured by Sirius Red staining and digital image analysis Partial: Rising cortical fibrosis > 10% but less than 25% No Response: Greater than 25% rise in cortical fibrosis over baseline levels-(if patient consents to repeat kidney biopsy)

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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
  • AST or 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00498368

Locations
United States, California
Stanford University
San Francisco, California, United States, 94304
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, North Carolina
University of North Carolina, Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
The University of Ohio
Columbus, Ohio, United States, 43210-1063
Sponsors and Collaborators
Mayo Clinic
Ohio State University
Stanford University
University of North Carolina, Chapel Hill
Columbia University
Investigators
Principal Investigator: Fernando C. Fervenza, M.D. Mayo Clinic
  More Information

No publications provided

Responsible Party: Fernando Fervenza, M.D., Ph.D, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00498368     History of Changes
Other Study ID Numbers: 07-001944
Study First Received: July 9, 2007
Last Updated: November 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
Estimated GFR
Proteinuria
Renal Fibrosis

Additional relevant MeSH terms:
Glomerulonephritis, IGA
Kidney Diseases
Autoimmune Diseases
Glomerulonephritis
Immune System Diseases
Nephritis
Urologic Diseases
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014