A Study on The Safety of Administering Rituximab at A More Rapid Rate in Patients With Rheumatoid Arthritis (RATE-RA)

A Multicenter, Open-label, Single-arm Study to Evaluate the Safety Administering Rituximab at a More Rapid Infusion Rate in Patients With Rheumatoid Arthritis

This study was designed to evaluate the safety of administering rituximab at a more rapid infusion rate in patients with moderate to severe rheumatoid arthritis who have had an inadequate response to biopharmaceuticals that treat diseases by interfering with tumor necrosis factor (anti-TNF therapies), and were receiving methotrexate therapy for more than eight weeks.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: rituximab; Drug: methotrexate; Drug: methylprednisolone; Drug: acetaminophen; Drug: antihistamine

• Study Type: Interventional
• Enrollment (Actual): 351
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Uni Of Alabama,Birmingham; Medicine - Rheumatology
    • Tuscaloosa, Alabama, United States, 35406
      • Clnical & Translational Reseach Center for Alabama, PC
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • ArthroCare, Arthritis Care; and Research P.C.
    • Phoenix, Arizona, United States, 85027
      • Valley Arthritis Care
    • Tucson, Arizona, United States, 85704
      • Catalina Pointe Rheumatology
  • California
    • Covina, California, United States, 91723
      • Medvin Clinical Research
    • La Mesa, California, United States, 91942
      • Triwest Research Associates
    • Los Angeles, California, United States, 90048
      • Medvin Clinical Research
    • Murrieta, California, United States, 92563
      • Brigid Freyne-Private Practice; Internal Medicine, Rheum
    • Palm Desert, California, United States, 92260
      • Desert Medical Advances; Rheumatology
    • San Diego, California, United States, 92108
      • San Diego Arthritis Med Clnc
    • Santa Maria, California, United States, 93454
      • Pacific Arthritis Ctr Med Grp
    • Upland, California, United States, 91786
      • Inland Rheumatology; Clinical Trials, Inc.
    • Whittier, California, United States, 90606
      • Medvin Clinical Research
  • Colorado
    • Colorado Springs, Colorado, United States, 80920
      • Arthritis Assoc & Osteoporosis; Ctr of Colorado Springs
    • Denver, Colorado, United States, 80230-7127
      • Denver Arthritis Clinic
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
      • Rheum & Internal Med Assoc-Bri
    • Hamden, Connecticut, United States, 06518
      • Arthritis & Osteoporosis Center Pc
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Rheumatolgy Consultants of Deleware
    • Newark, Delaware, United States, 19713
      • Javed Rheumatology Associates, Inc.
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatism; Disease Specialities
    • Lake Mary, Florida, United States, 32746
      • Florida Arthritis Center, PI
    • Orlando, Florida, United States, 32804
      • Omega ResearchConsultants LLC
    • Ormond Beach, Florida, United States, 32174
      • Millenium Research
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Center Palm Harbor
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Rsrch of Florida, Inc.
    • South Miami, Florida, United States, 33143
      • Center For Arthritis; Research Dept
    • Tampa, Florida, United States, 33612
      • University of South Florida
    • Zephyrhills, Florida, United States, 33613
      • Florida Medical Clinic; Clinical Research
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • Parris & Associates
  • Idaho
    • Boise, Idaho, United States, 83702
      • St. Luke's Intermountain Research Center
    • Idaho Falls, Idaho, United States, 83404
      • Institute of Arthritis Research
  • Illinois
    • Moline, Illinois, United States, 61265
      • Quad City Rheumatology, Sc
  • Iowa
    • Cedar Rapids, Iowa, United States, 52401
      • Physician'S Clinic of Iowa
  • Kentucky
    • Lexington, Kentucky, United States, 40515
      • Bluegrass Comm Research, Inc.
  • Maryland
    • Cumberland, Maryland, United States, 21502
      • Klein & Associates, M.D. P.A.
    • Hagerstown, Maryland, United States, 21740
      • Klein & Associates, M.D., P.A.
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • St. Luke's Hospital Association of Duluth
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Jackson Arthritis Clinic
    • Flowood, Mississippi, United States, 39232
      • Arthritis and Osteoporosis; Treatment and Research Center
    • Tupelo, Mississippi, United States, 38801
      • North Mississippi Med Clinics, Inc.
  • Missouri
    • Florissant, Missouri, United States, 63031
      • David S Rosenberg
  • Nevada
    • Reno, Nevada, United States, 89502
      • Arthritis Center of Reno
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Rheumatology Research Group
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Rheumatology Associates Of New Jersey
  • New York
    • Albany, New York, United States, 12203
      • The Center for Rheumatology
    • Brooklyn, New York, United States, 11201
      • Arthritis & Osteoporosis Center
    • New York, New York, United States, 10003
      • NYU Center for Musculoskeletal Care
    • Orchard Park, New York, United States, 14127
      • Buffalo Rheumatology Associates
    • Plainview, New York, United States, 11803
      • Office of Premier Chatpar Md
    • Rochester, New York, United States, 14618
      • AAIR Research Center
    • Smithtown, New York, United States, 11787
      • Rheumatology Associates of Long Island
    • Syracuse, New York, United States, 13210
      • Arthritis Health Associates; Clinical Research
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Carolina Bone & Joint P.A.
    • Charlotte, North Carolina, United States, 28207
      • Arth&OsteoConsof theCarolinas-Charlotte
    • Charlotte, North Carolina, United States, 28210
      • Box Arthritis & Rheumatology
    • Greenville, North Carolina, United States, 27834
      • Physicians East PA
    • Raleigh, North Carolina, United States, 27617
      • Shanahan Rheumatology & Immunology, PLLC
  • Ohio
    • Akron, Ohio, United States, 44333
      • Crystal Arthritis Center, Inc.
    • Columbus, Ohio, United States, 43203
      • CarePoint East
    • Dayton, Ohio, United States, 45402
      • Stat Research, Inc
    • Middleburg Heights, Ohio, United States, 44130
      • Paramount Medical Research
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Lion Research
    • Oklahoma City, Oklahoma, United States, 73103
      • Arthritis and Rheumatology; Center of Oklahoma PLLC
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • East Penn Rheumatology Associates, Pc
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
    • Perkasie, Pennsylvania, United States, 18944
      • Pivotal Clinical Research, Llc
    • Philadelphia, Pennsylvania, United States, 19152
      • Arthritis Group
    • Willow Grove, Pennsylvania, United States, 19090
      • Rheumatic Disease Associates; Clinical Research Unit
    • Wyomissing, Pennsylvania, United States, 19610
      • Clinical Research Center of Reading
    • Wyomissing, Pennsylvania, United States, 19610
      • Pennsylvania Regional Center for Arthritis and Osteoporosis Research
  • South Carolina
    • Charleston, South Carolina, United States, 29407
      • Rheumatology Associates
    • Charleston, South Carolina, United States, 29406
      • Low Country Rheumatology, PA
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • West Tennessee Research Institute
    • Memphis, Tennessee, United States, 38119
      • Ramesh Gupta - PP
  • Texas
    • Amarillo, Texas, United States, 79124
      • Amarillo Center for Clinical Research
    • Austin, Texas, United States, 78758
      • Lovelace Scientific Resources Inc.
    • Corpus Christi, Texas, United States, 78404
      • Adriana Pop-Moody MD Clinic PA
    • Dallas, Texas, United States, 75246
      • Arthritis Centers of Texas
    • Mesquite, Texas, United States, 75150
      • Southwest Rheumatology
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Arthritis Clinic of Northern Virginia
  • Washington
    • Kennewick, Washington, United States, 99336
      • Apex Clinical Research
    • Seattle, Washington, United States, 98133
      • Seattle Arthritis Clinic
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest, Spokane
    • Tacoma, Washington, United States, 98405
      • Cedar Medical Center
  • Wisconsin
    • Glendale, Wisconsin, United States, 53217
      • Rheumatic Disease Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Adult patients, ≥ 18 years of age
• Rheumatoid arthritis of ≥ 6 months duration, diagnosed according to the revised 1987 American College of Rheumatology criteria
• Inadequate response to at least one approved anti-TNF agent (adalimumab, etanercept, infliximab, golimumab, or certolizumab)
• Patients who have received 1 to 2 prior courses of rituximab (RTX) may be enrolled, provided their most recent course of RTX occurred over 6 months but no more than 9 months prior to baseline. The RTX dosage must have been two 1000 mg infusions per course administered at the standard approved rate
• Methotrexate treatment between 10 and 25 mg/week (oral or parenteral) for at least 8 weeks immediately prior to baseline

Key Exclusion Criteria:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned surgery within 6 months following baseline
• Rheumatic autoimmune disease other than rheumatoid arthritis
• Functional class IV as defined by American College of Rheumatology (ACR) criteria
• Prior history of or current inflammatory joint disease other than rheumatoid arthritis
• History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
• Previous serious infusion reaction to any prior biologic therapy
• Known active current or history of recurrent infection
• Evidence of chronic hepatitis B or C infection
• Pregnant or lactating women
• Body weight of > 150 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rituximab; Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.

Drug: rituximab; 1000 mg in 250 mL intravenous infusion; Other Names: Rituxan®; MabThera®; Drug: methotrexate; 10 to 25 mg/week (oral or parenteral); Drug: methylprednisolone; 100 mg methylprednisolone administered by slow intravenous infusion at least 30 minutes prior to the start of each study drug infusion; Drug: acetaminophen; 1 gram acetaminophen administered orally 30 to 60 minutes prior to the start of each study drug infusion; Drug: antihistamine; 50 mg diphenhydramine hydrochloride or equivalent dose of alternate antihistamine administered orally 30 to 60 minutes prior to the start of each study drug infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Any Infusion-related Reaction (IRR) Associated With the Second Rituximab Infusion	The primary criterion for assessing safety of the faster infusion was the incidence of infusion related reaction (IRRs). IRRs were adverse events (AEs) that occurred within 24 hours of beginning infusion that were among a pre-specified list of preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA). "Incidence" is defined as the percentage of participants experiencing an IRR.	Within 24 hours of beginning infusion on Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Any Serious IRR (SIRR) Associated With the Second Rituximab Infusion	A serious infusion-related reaction (SIRR) is an IRR that meets the definition of a serious adverse event. A serious adverse event (SAE) is any experience that suggests a significant hazard, contraindication, side effect or precaution.	Within 24 hours of beginning infusion on Day 15
Percentage of Participants Experiencing Any IRR or SIRR Associated With the Third Rituximab Infusion	IRRs are AEs that occurred within 24 hours of beginning infusion that were included on a pre-specified list of MedDRA preferred terms, and an SIRR is an IRR that suggests a significant hazard, contraindication, side effect or precaution.	Within 24 hours of beginning infusion on Day 168
Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Second Rituximab Infusion	The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0), where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: - Grade 3 means "Severe", indicating considerable interference with the patient's daily activities; medical intervention/therapy required; and hospitalization possible. - Grade 4 means "Life-threatening, Disabling", based on extreme limitation in activity; significant medical intervention/therapy required, and hospitalization probable.	Within 24 hours of beginning infusion on Day 15
Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Second Rituximab Infusion	Participants who experienced a moderate or serious IRR had their infusion interrupted immediately and received aggressive symptomatic treatment. The CTCAE includes the following severity descriptions: - "Moderate" means mild to moderate interference with the patient's daily activities, no or minimal medical intervention/therapy required; - "Severe" means considerable interference with the patient's daily activities, medical intervention/therapy required, hospitalization possible. If the IRR was moderate, the infusion was not to be restarted before all the symptoms disappeared, and then at half the rate. If the participant tolerated the reduced rate for 30 minutes, the infusion rate was increased to the next rate on the protocol-specified infusion schedule. If the symptoms did not resolve with treatment, the participant was withdrawn from the treatment period of the study. Participants who experienced a severe IRR to rituximab treatment were discontinued from the study.	During the infusion (a 2-hour period) on Day 15
Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Third Rituximab Infusion	The intensity of AEs experienced within 24 hours of beginning infusion were graded on NCI's CTCAE (v. 4.0) intensity scale from Grade 1 ("Mild") to Grade 5 ("Death"). Grade 3 AEs are "Severe" and Grade 4 AEs are "Life-threatening, Disabling".	Within 24 hours of beginning infusion on Day 168
Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Third Rituximab Infusion	Participants who experienced a moderate or serious IRR had their infusion interrupted immediately and received aggressive symptomatic treatment. The CTCAE includes the following severity descriptions: - "Moderate" means mild to moderate interference with the patient's daily activities, no or minimal medical intervention/therapy required; - "Severe" means considerable interference with the patient's daily activities, medical intervention/therapy required, hospitalization possible. If the IRR was moderate, the infusion was not to be restarted before all the symptoms disappeared, and then at half the rate. If the participant tolerated the reduced rate for 30 minutes, the infusion rate was increased to the next rate on the protocol-specified infusion schedule. If the symptoms did not resolve with treatment, the participant was withdrawn from the treatment period of the study. Participants who experienced a severe IRR to rituximab treatment were discontinued from the study.	During the infusion (a 2-hour period) on Day 168

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2011
• Primary Completion (Actual): January 6, 2013
• Study Completion (Actual): January 6, 2013

Study Registration Dates

• First Submitted: June 24, 2011
• First Submitted That Met QC Criteria: June 24, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Actual): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 5, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antipyretics; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Histamine Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methylprednisolone; Rituximab; Acetaminophen; Methotrexate; Histamine H1 Antagonists; Histamine Antagonists
• Other Study ID Numbers: ML25641