A Study to Evaluate the Safety of Rituximab Retreatment in Subjects With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe systemic lupus erythematosus (SLE). The primary efficacy endpoint of the trial will be evaluated at 52 weeks.

Official Title
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Randomized, Double-blind, Placebo-controlled, Multicenter, Phase II/III Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With Moderate to Severe Systemic Lupus Erythematosus

Conditions
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Lupus Erythematosus, Systemic

Intervention / Treatment
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* Drug: Rituximab
* Drug: Placebo
* Drug: Prednisone
* Drug: Acetaminophen
* Drug: Diphenhydramine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of systemic lupus erythematosus (SLE). Active disease at screening. Stable use of one immunosuppressive drug. Use of an antimalarial drug. For subjects of reproductive potential (males and females), use of a reliable means of contraception throughout their study participation. Exclusion Criteria: Unstable patients 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. Active moderate to severe glomerulonephritis. 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. Lack of peripheral venous access. Pregnant women or nursing (breast feeding) mothers. History of severe, allergic, or anaphylactic reactions to humanized or murine monoclonal antibodies. Significant, uncontrolled medical disease in any organ system not related to SLE that in the investigator's opinion would preclude subject participation. Concomitant conditions that require oral or systemic corticosteroid use. Known human immunodeficiency virus (HIV) infection. Known active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics. History of deep space infection. History of serious recurrent or chronic infection. History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ. Active alcohol or drug abuse, or history of alcohol or drug abuse. Major surgery. Previous treatment with CAMPATH-1H antibody. Previous treatment with any B cell-targeted therapy. Treatment with any investigational agent within 28 days of screening (Day -7) or 5 half-lives of the investigational drug (whichever is longer). Receipt of a live vaccine within 28 days prior to screening. Intolerance or contraindication to oral or IV corticosteroids. Use of a new immunosuppressive drug prior to screening or change in dose of ongoing immunosuppressive drug prior to screening. Prednisone dose of ≥ 1 mg/kg/day prior to screening. Treatment with cyclophosphamide or a calcineurin inhibitor. Treatment with a second immunosuppressive or immunomodulatory drug. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x the upper limit of normal.

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 1000 mg + prednisone<br>Participants will receive rituximab 1000 mg intravenously on Days 1, 15, 168, and 182. Participants will also receive an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants will also receive acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion. | Drug: Rituximab<br>* Rituximab will be supplied as a sterile liquid for IV administration.<br>* Other names: Zytux;Drug: Prednisone<br> <br> Drug: Acetaminophen<br> <br> Drug: Diphenhydramine<br> <br> |
| Placebo Comparator: Placebo + prednisone<br>Participants will receive placebo intravenously on Days 1, 15, 168, and 182. Participants will also receive an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants will also receive acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion. | Drug: Placebo<br>* Placebo will be supplied as a sterile liquid for IV administration.<br>Drug: Prednisone<br> <br> Drug: Acetaminophen<br> <br> Drug: Diphenhydramine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | The BILAG Index measures clinical disease activity in Systemic Lupus Erythematosus (SLE). A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24; PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+>=2Bs, or>=2 As, or>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. | From baseline to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-adjusted Area Under The Curve Minus Baseline (AUCMB) of BILAG Score Over The 52-week Treatment Period | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. The AUCMB of BILAG Score Over 52 Weeks was calculated as: 1. Calculate the AUC of the BILAG global score versus time (in days) by 52 weeks. 2. Calculate the Time-Adjusted AUC by dividing the AUC by the number of days a patient was on the study. 3. Minus the Time-Adjusted AUC by the baseline BILAG global score | From baseline to 52 weeks | 
| Number of Participants Who Achieved an MCR (Excluding PCR) | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+>=2Bs, or>=2 As, or>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. | From baseline to 52 weeks | 
| Number of Participants Who Achieved a PCR (Including MCR) | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+>=2Bs, or>=2 As, or>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. MCR = participants who achieved BILAG C or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. | From baseline to 52 Weeks | 
| Number of Participants Who Achieved a BILAG C or Better in All Domains | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. | 24 weeks | 
| Time to First Moderate or Severe Flare | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. A severe flare = participants had BILAG A score(s) present in one or more domains or BILAG B scores present in three or more domains at the same visit following a visit of inactive disease state defined above. A moderate flare = participants had only BILAG B scores present in two domains at the same visit following a visit of inactive disease state. | 52 weeks | 
| Change in SLE Expanded Health Survey Physical Function Score From Baseline | Short Form (36) with additional questions specific to lupus (scale = 0-100; with 100 representing the highest level of functioning possible) to measure the ability of rituximab to improve quality of life. A positive value for this outcome measure indicates that symptoms have improved. | From baseline to 52 weeks | 
| Number of Participants Who Achieved an MCR in The ITT Population | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. | From Weeks 24 to 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituxan, SLE, Lupus