Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Efficacy and Safety of Rituximab in Subjects with ISN/RPS Class III
or IV Lupus Nephritis
PI: Gerald Appel, MD
The primary objective of this study is 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 (LN), as assessed by improvements in renal function, urinary sediment and proteinuria.
The secondary objectives of this study are to evaluate the efficacy of rituximab in combination with MMF compared with placebo in combination with MMF in subjects diagnosed with ISN/RPS 2003 Class III or IV LN to:
*Induce an early complete renal response and maintain it to week 52
*Induce a complete renal response at week 52
*Reduce nephrotic-range proteinuria
*Decrease overall systemic lupus erythematosus (SLE) disease activity
*Induce an early partial renal response and maintain it
*Improve measures of quality of life
*Reduce autoantibody levels
Inclusion Criteria:
Subjects must meet all of the following criteria to be eligible for study entry:
*Ability and willingness to provide written informed consent and comply with the schedule of protocol assessments
*Diagnosis of SLE according to current ACR criteria (at least four criteria must be present, one of which must be a positive ANA at a titer of ≥ 1:160 at any time)
* Diagnosis of ISN/RPS 2003 Class III or IV LN, with either active or active/chronic disease
*Renal biopsy must have been done within the 12 months prior to screening. (If the biopsy was performed > 3 months prior to screening, then an active urinary sediment, as evidenced by ≥ 10 RBCs/HPF or the presence of red blood cell casts, must also be present.)
* Proteinuria, as defined by a urine protein to creatinine ratio > 1.0
* 16-75 years of age
* For subjects of reproductive potential (males and females), use of effective contraception during the study
Exclusion Criteria:
a. Criteria Related to SLE
*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
* Presence of rapidly progressive glomerulonephritis (defined by the presence of crescent formation in ≥ 50% of glomeruli assessed on renal biopsy or doubling of serum creatinine within 12 weeks of screening)
* > 50% of glomeruli with sclerosis on renal biopsy
* > 50% interstitial fibrosis on renal biopsy
* Estimated GFR < 30 mL/min per 1.73 m2 (as calculated by the abbreviated
MDRD equation, below) at screening or end-stage renal disease requiring dialysis or transplant
*Estimated GFR (mL/min per 1.73 m2) = 186 × (serum creatinine)−1.154×(age)−0.203
× (0.742 if subject is female) × (1.210 if subject is Black)
* 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
b. Criteria Related to General Health
* Lack of peripheral venous access (peripherally inserted central catheters will be allowed for rituximab/placebo infusions but must be removed after the second study drug infusion of each course)
* 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 (e.g., asthma, Crohn’s disease) that require oral or systemic corticosteroid use in the 52 weeks prior to screening
Use of inhaled or topical corticosteroids will be allowed.
* History of renal transplant
* Known 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 8 weeks of the screening visit or oral anti-infectives within 2 weeks prior to the screening visit.
* 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)
c. Criteria Related to Medications
* Treatment with CYC or calcineurin inhibitors within the 90 days prior to screening
* Use of MMF at a dose ≥ 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 corticosteroids at a dose higher than 20 mg/day for longer than the 14 days prior to screening
* Previous treatment with CAMPATH-1H
* Previous treatment with a B-cell targeted therapy (e.g., anti-CD20, anti-CD22, anti-BlyS)
* Treatment with any investigational agent within 28 days of the start of the screening period or 5 half-lives of the investigational drug (whichever is longer)
* Treatment with any biologic agent
* Receipt of a live vaccine within the 28 days prior to screening
* Intolerance or contraindication to oral or IV corticosteroids
d. Criteria Related to Laboratory Values
* AST or ALT > 2.5 × the upper limit of normal
* Amlyase or lipase > 2 × the upper limit of normal
* Neutrophils < 1.5 × 103/μL
* Positive hepatitis B sAg or hepatitis C serology
* Hemoglobin < 7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE
* Platelet count < 10,000/μL
* Positive serum human chorionic gonadotropin (hCG), as measured prior to the first rituximab infusion