A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Class III or IV Lupus Nephritis

Condition(s) targeted: Lupus Nephritis

Intervention: Rituximab (Drug); Placebo (Drug); Mycophenolate mofetil (Drug); Methylprednisolone (Drug); Diphenhydramine (Drug); Acetaminophen (Drug); Prednisone (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Genentech, Inc.

Official(s) and/or principal investigator(s):
Paul Brunetta, MD, Study Director, Affiliation: Genentech, Inc.

This was a Phase III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of rituximab in combination with mycophenolate mofetil (MMF) compared with placebo in combination with MMF in subjects diagnosed with International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Class III or IV lupus nephritis.

Official title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With ISN/RPS Class III or IV Lupus Nephritis

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Percentage of Participants Who Achieved a Complete Renal Response (CRR), a Partial Renal Response (PRR), or no Renal Response (NRR) at Week 52

Secondary outcome:

Percentage of Participants Who Achieved a Complete Renal Response at Week 24 and Maintained it to Week 52

Percentage of Participants Who Achieved a Complete Renal Response at Week 52

Percentage of Participants With a Baseline Urine Protein to Creatinine Ratio of > 3.0 Who Achieved a Urine Protein to Creatinine Ratio of < 1.0 at Week 52

British Isles Lupus Assessment Group (BILAG) Index Score Over 52 Weeks

Time to Achieve a Complete Renal Response

Change From Baseline in the Systemic Lupus Erythematosus Expanded Health Survey Physical Function Score at Week 52

Change From Baseline in Anti-double-stranded DNA at Week 52

Change From Baseline in C3 and C4 Complement Levels at Week 52

Detailed description: In addition to receiving study drug (rituximab or placebo), participants in each treatment group received mycophenolate mofetil at a starting dose of 1500 mg/day IV in 3 divided doses and were titrated up by 500 mg/week to 3000 mg/day by Week 4, as tolerated. Participants in each treatment group also received methylprednisolone 1000 mg IV prior to and 3 days following the first study drug infusion and methylprednisolone 100 mg IV prior to the other study drug infusions. Participants in each treatment group also received diphenhydramine 50 mg orally and acetaminophen 1000 mg orally 30-60 minutes prior to each study drug infusion. From Days 2 to 16, participants in each treatment group received prednisone 0. 75 mg/kg/day orally (maximum dose of 60 mg) except on the day of the second methylprednisolone dose. On Day 16, a taper was initiated to achieve a dose of 10 mg/day by Week 16.

Minimum age: 16 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Diagnosis of systemic lupus erythematosus (SLE) according to current American College

of Rheumatology (ACR) criteria.

- Diagnosis of International Society of Nephrology/Renal Pathology Society (ISN/RPS)

2003 Class III or IV lupus nephritis (LN), with either active or active/chronic disease.

- Proteinuria.

- 16-75 years of age.

Exclusion Criteria:

- Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis,

stroke or stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from SLE.

- Unstable subjects with thrombocytopenia experiencing or at high risk for developing

clinically significant bleeding or organ dysfunction requiring therapies such as plasmapheresis or acute blood or platelet transfusions.

- Lack of peripheral venous access.

- Pregnancy or lactation.

- History of severe allergic or anaphylactic reactions to monoclonal antibodies.

- Significant or uncontrolled medical disease in any organ system not related to SLE or

LN, which, in the investigator's opinion, would preclude subject participation.

- Concomitant chronic conditions, excluding SLE (eg, asthma, Crohn's disease) that

require oral or systemic corticosteroid use in the 52 weeks prior to screening.

- History of renal transplant.

- Known human immunodeficiency virus (HIV) infection.

- Known active infection of any kind (but excluding fungal infection of nail beds) or

any major episode of infection requiring hospitalization or treatment with intravenous anti-infectives within 4 weeks of randomization or oral anti-infectives within 2 weeks of randomization.

- History of deep space infection within 1 year of screening.

- History of serious recurrent or chronic infection.

- History of cancer, including solid tumors, hematological malignancies, and carcinoma

in situ (except basal cell carcinomas of the skin that have been treated or excised and have resolved).

- Currently active alcohol or drug abuse or history of alcohol or drug abuse within 52

weeks prior to screening.

- Major surgery requiring hospitalization within 4 weeks of screening (excluding

diagnostic surgery).

- Treatment with cyclophosphamide or calcineurin inhibitors within the 90 days prior to

screening.

- Use of mycophenolate mofetil (MMF) at a dose of > 2 grams daily for longer than the

90 days prior to screening.

- Intolerance or history of allergic reaction to MMF.

- Intolerance or history of allergic reaction to both angiotensin-converting enzyme

(ACE) inhibitors and angiotensin-receptor blockers.

- Use of oral prednisone (or corticosteroid equivalent) at a dose of > 20 mg/day for

longer than the 14 days prior to screening.

- Previous treatment with CAMPATH-1H (alemtuzumab).

- Previous treatment with a B-cell targeted therapy.

- Treatment with any investigational agent (including biologic agents approved for

other indications) within 28 days of the start of the screening period or 5 half-lives of the investigational drug (whichever is longer).

- Receipt of a live vaccine within the 28 days prior to screening.

- Intolerance or contraindication to oral or IV corticosteroids.

- Current therapy with a nonsteroidal anti-inflammatory agent.

- Positive hepatitis B sAg or hepatitis C serology.

Starting date: January 2006
Last updated: January 6, 2015