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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Placebo
* Drug: Mycophenolate mofetil
* Drug: Methylprednisolone
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. They also received mycophenolate mofetil, methylprednisolone, diphenhydramine, acetaminophen, and prednisone; see the Detailed Description for details. | Drug: Rituximab<br>* Rituximab was provided as a sterile solution for injection.<br>* Other names: Zytux;Drug: Mycophenolate mofetil<br> <br> * Other names: CellCept;Drug: Methylprednisolone<br> <br> Drug: Diphenhydramine<br> <br> Drug: Acetaminophen<br> <br> Drug: Prednisone<br> <br> |
| Placebo Comparator: Placebo<br>Participants received placebo intravenously (IV) on Days 1, 15, 168, and 182. They also received mycophenolate mofetil, methylprednisolone, diphenhydramine, acetaminophen, and prednisone; see the Detailed Description for details. | Drug: Placebo<br>* Placebo was provided as a sterile solution for injection.<br>Drug: Mycophenolate mofetil<br> <br> * Other names: CellCept;Drug: Methylprednisolone<br> <br> Drug: Diphenhydramine<br> <br> Drug: Acetaminophen<br> <br> Drug: Prednisone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Complete Renal Response (CRR), a Partial Renal Response (PRR), or no Renal Response (NRR) at Week 52 | A participant had a CRR if they met the following 3 criteria: (1) Normalization of serum creatinine (SC) as evidenced by a SC level ≤ the upper limit of the normal range of central laboratory values or a SC level ≤ 15% greater than Baseline, if Baseline SC was within the normal range of the central laboratory values; (2) Inactive urinary sediment (as evidenced by < 5 red blood cells/high-power field (RBCs/HPF) and absence of red cell casts; (3) Urinary protein (UP) to creatinine ratio (CR) < 0.5. A participant had a PRR if they met the following 3 criteria: (1) A SC level ≤ 15% above Baseline; (2) RBCs/HPF ≤ 50% above Baseline and no RBC casts; (3) 50% improvement in the UP to CR, with 1 of the following conditions met: If the Baseline UP to CR was ≤ 3.0, then a UP to CR of < 1.0 or if the Baseline UP to CR was > 3.0, then a UP to CR of ≤ 3.0. A participant had a NRR if they did not achieve either a CRR or PRR. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Complete Renal Response at Week 24 and Maintained it to Week 52 | A participant had a complete renal response if they met the following 3 criteria: (1) Normalization of serum creatinine as evidenced by a serum creatinine level ≤ the upper limit of the normal range of central laboratory values or a serum creatinine level ≤ 15% greater than Baseline, if Baseline serum creatinine was within the normal range of the central laboratory values; (2) Inactive urinary sediment (as evidenced by < 5 red blood cells/high-power field and absence of red cell casts; (3) Urinary protein to creatinine ratio < 0.5. | Week 24 to Week 52 | 
| Percentage of Participants Who Achieved a Complete Renal Response at Week 52 | A participant had a complete renal response if they met the following 3 criteria: (1) Normalization of serum creatinine as evidenced by a serum creatinine level ≤ the upper limit of the normal range of central laboratory values or a serum creatinine level ≤ 15% greater than Baseline, if Baseline serum creatinine was within the normal range of the central laboratory values; (2) Inactive urinary sediment (as evidenced by < 5 red blood cells/high-power field and absence of red cell casts; (3) Urinary protein to creatinine ratio < 0.5. | 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 |  | Baseline to Week 52 | 
| British Isles Lupus Assessment Group (BILAG) Index Score Over 52 Weeks | The BILAG Index assesses 86 clinical signs and symptoms and laboratory measures of systemic lupus erythematosus in 8 organ system domains: General, mucocutaneous, neurological, musculoskeletal, cardiorespiratory, vasculitis, renal, and hematologic. Most of the 86 items are rated on the following scale: 0=Not present, 1=Improving, 2=Same, 3=Worse, 4=New. Some items are rated as either Yes or No. A single alphabetic score of A (very active) through E (not or never active) for each of the 8 domains is determined from the rating of the individual items in each domain. The total BILAG score is the sum of the scores of the 8 domains where A=9, B=3, C=1, D=0, and E=0. The total score ranges from 0 to 72 with a higher score indicating greater lupus activity. To calculate a BILAG score over the 52 week treatment period of the study, the area under the response-time curve of BILAG scores assessed every 4 weeks was divided by the number of days in the time curve minus the Baseline BILAG score. | Baseline to Week 52 | 
| Time to Achieve a Complete Renal Response |  | Baseline to Week 52 | 
| Change From Baseline in the Systemic Lupus Erythematosus Expanded Health Survey Physical Function Score at Week 52 | The systemic lupus erythematosus Expanded Health Survey is based on the Short Form 36 Health survey with additional questions specific to lupus. The physical function component score of the survey can range from 0-100. A higher score indicates better health. A positive change score indicates improvement. | Baseline to Week 52 | 
| Change From Baseline in Anti-double-stranded DNA at Week 52 |  | Baseline to Week 52 | 
| Change From Baseline in C3 and C4 Complement Levels at Week 52 |  | Baseline to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Class IV LN, Lupus, LUNAR, LN