Clinical trial NCT00282347: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lupus Nephritis
Keywords: Class IV LN
Lupus
LUNAR
LN
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2006-01-26
Enrollment: 144
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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.

Primary outcomes:
measure: Percentage of Participants Who Achieved a Complete Renal Response (CRR), a Partial Renal Response (PRR), or no Renal Response (NRR) at Week 52
timeFrame: Week 52
Secondary outcomes:
measure: Percentage of Participants Who Achieved a Complete Renal Response at Week 24 and Maintained it to Week 52
timeFrame: Week 24 to Week 52
measure: Percentage of Participants Who Achieved a Complete Renal Response at Week 52
timeFrame: Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: British Isles Lupus Assessment Group (BILAG) Index Score Over 52 Weeks
timeFrame: Baseline to Week 52
measure: Time to Achieve a Complete Renal Response
timeFrame: Baseline to Week 52
measure: Change From Baseline in the Systemic Lupus Erythematosus Expanded Health Survey Physical Function Score at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Anti-double-stranded DNA at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in C3 and C4 Complement Levels at Week 52
timeFrame: Baseline to Week 52
Other outcomes:
Locations:
Study officials:
affiliation: Genentech, Inc.
name: Paul Brunetta, MD
role: STUDY_DIRECTOR
References:
citation: Gomez Mendez LM, Cascino MD, Garg J, Katsumoto TR, Brakeman P, Dall'Era M, Looney RJ, Rovin B, Dragone L, Brunetta P. Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis. Clin J Am Soc Nephrol. 2018 Oct 8;13(10):1502-1509. doi: 10.2215/CJN.01070118. Epub 2018 Aug 8.
citation: Wolf BJ, Spainhour JC, Arthur JM, Janech MG, Petri M, Oates JC. Development of Biomarker Models to Predict Outcomes in Lupus Nephritis. Arthritis Rheumatol. 2016 Aug;68(8):1955-63. doi: 10.1002/art.39623.
citation: Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G; LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012 Apr;64(4):1215-26. doi: 10.1002/art.34359. Epub 2012 Jan 9.