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

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

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.

Study Overview

• Status: Completed
• Conditions: Lupus Erythematosus, Systemic
• Intervention / Treatment: Drug: Prednisone; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Rituximab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 262
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A1M4
      • Univ of Manitoba, Health Scien; Arthritis Centre
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Health Care Centre
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ of Alabama School of Med; Clinical Immun Rheumatology
    • Huntsville, Alabama, United States, 35801
      • Rheumatology Assoc of North AL
  • Arizona
    • Paradise Valley, Arizona, United States, 85253
      • Arizona Arthritis & Rheumatology Research, PLLC
  • California
    • La Jolla, California, United States, 92037
      • Univ of California, San Diego
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90025
      • Univ of Calif., Los Angeles; Rheumatology
    • Palo Alto, California, United States, 94304
      • Stanford University Med Ctr;Div of Immunology/Rheumatology
    • San Francisco, California, United States, 94143-0111
      • Univ of Calif, San Francisco; Rheumatology
    • San Leandro, California, United States, 94578
      • Eden Medical Center San Leandro Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatism; Disease Specialities
    • Jupiter, Florida, United States, 33458
      • Family Arthritis Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory Uni ; Division of Rheumatology
  • Idaho
    • Boise, Idaho, United States, 83702
      • Intermountain Research Center
    • Coeur d'Alene, Idaho, United States, 83814
      • Coeur D'Alene Arthritis Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60612
      • Rheumatology Associates
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Tri-State Arth & Rheum Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Univ of Kansas Medical Center; Allergy/Clin Imm/Rheum
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Cancer Institute
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • LA State Univ; Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins Uni
    • Wheaton, Maryland, United States, 20902
      • Center For Rheumatology & Bone Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • TUFTS - New England Medical Center
    • Boston, Massachusetts, United States, 02215-5501
      • Dana-Farber Cancer Institute; Rheumatology
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Brighton, Michigan, United States, 48116
      • Michigan Arthritis Rsrch Ctr
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University; Rheumatology Division
  • New York
    • Albany, New York, United States, 12206
      • Center for Rheumatology, State Uni. of New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center.
    • Lake Success, New York, United States, 11042
      • NS-LIJ Health Systems; Rheum-Allergy Clin Immu
    • Manhasset, New York, United States, 11030
      • Feinstein Institute for Medical Research
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • New York, New York, United States, 10003
      • NYU-Hosp for Joint Diseases; Rheum and Med
    • Orchard Park, New York, United States, 14127
      • Buffalo Rheumatology Associates
    • Plainview, New York, United States, 11803
      • Long Island Osteo/Arth Center
    • Rochester, New York, United States, 14642
      • University of Rochester - Strong Memorial Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Hospitals Department of Pharmacy; Investigational Drug Services
    • Durham, North Carolina, United States, 27710
      • Duke Medical Center
    • Greenville, North Carolina, United States, 27834
      • Physicians East PA
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University; Division of Nephrology
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Medical Research Foundation
    • Oklahoma City, Oklahoma, United States, 73103
      • Bone and Joint Hospital at St. Anthony Research Department
    • Tulsa, Oklahoma, United States, 74104
      • Oklahoma Center For Arthritis Therapy & Research
  • Oregon
    • Portland, Oregon, United States, 97224
      • Portland Medical Associates
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • East Penn Rheumatology Associates, Pc
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Arthritis & Osteo Center
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Uni of Pennslyvania Medical Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical Univ of South Carolina
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Arthritis Associates PLLC
  • Texas
    • Dallas, Texas, United States, 75246
      • Arthritis Centers of Texas
    • Dallas, Texas, United States, 75231
      • Metroplex Clinical Research
    • Houston, Texas, United States, 77074
      • Houston Inst. For Clinical Research
    • Lubbock, Texas, United States, 79424
      • Arthritis & Osteoporosis Associates, LLP
    • Sugar Land, Texas, United States, 77479
      • Texas Research Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Med Ctr; Div of Ped Respiratory Med
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
    • Seattle, Washington, United States, 98104
      • Seattle Rheumatology Assoc; Swedish Rheumatology Research
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest, Spokane

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab 1000 mg + prednisone; 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: Prednisone; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Rituximab; Rituximab will be supplied as a sterile liquid for IV administration.; Other Names: Rituxan; MabThera; Zytux
Placebo Comparator: Placebo + prednisone; 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: Prednisone; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Placebo; Placebo will be supplied as a sterile liquid for IV administration.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Paul Brunetta, M.D., Genentech, Inc.

Publications and helpful links

General Publications

• Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010 Jan;62(1):222-33. doi: 10.1002/art.27233.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2005
• Primary Completion (Actual): August 25, 2008
• Study Completion (Actual): August 25, 2008

Study Registration Dates

• First Submitted: August 26, 2005
• First Submitted That Met QC Criteria: August 26, 2005
• First Posted (Estimate): August 30, 2005

Study Record Updates

• Last Update Posted (Actual): August 20, 2019
• Last Update Submitted That Met QC Criteria: August 2, 2019
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Lupus; Rituxan; SLE
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antipyretics; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Dermatologic Agents; Hypnotics and Sedatives; Anesthetics, Local; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Rituximab; Acetaminophen; Diphenhydramine; Promethazine; Prednisone
• Other Study ID Numbers: U2971g