A Study Of Tocilizumab in Patients With Moderate to Severe Active Rheumatoid Arthritis Who Have an Inadequate Response to or Are Unable to Tolerate Biologic and Non-Biologic Disease-modifying Antirheumatic Drugs (DMARDs)

October 19, 2012 updated by: Hoffmann-La Roche

Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients With Active Rheumatoid Arthritis on Background Non-biologic DMARDs and Monotherapy Who Have an Inadequate Response to Current Non-Biologic or Biologic DMARDs

This 3 arm randomized open label study will evaluate the safety, tolerability and efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis, who have had inadequate response to or are unable to tolerate DMARDs. The protocol incorporates risk mitigation strategies developed in partnership with the FDA to manage known and potential risks associated with the treatment of tocilizumab. Patients will be randomized to receive tocilizumab either 4 mg/kg intravenous (iv) or 8 mg/kg iv with concomitant non-biologic DMARDs, or 8 mg/kg iv without concomitant non-biologic DMARDs, every 4 weeks, for a total of 6 infusions. The anticipated time on study treatment is 3-12 months, and the target sample size is 500-1000 individuals.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

886

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Anniston, Alabama, United States, 36207
      • Birmingham, Alabama, United States, 35294
      • Birmingham, Alabama, United States, 35205
      • Huntsville, Alabama, United States, 35801
      • Mobile, Alabama, United States, 36608
      • Montgomery, Alabama, United States, 36111
      • Tuscaloosa, Alabama, United States, 35406
    • Arizona
      • Hot Springs, Arizona, United States, 71913
      • Paradise Valley, Arizona, United States, 85253
      • Peoria, Arizona, United States, 85381
      • Scottsdale, Arizona, United States, 85258
      • Scottsdale, Arizona, United States, 85251
      • Tucson, Arizona, United States, 85704
    • Arkansas
      • Fayetteville, Arkansas, United States, 27203
      • Fort Smith, Arkansas, United States, 72903
      • Jonesboro, Arkansas, United States, 72401
      • Little Rock, Arkansas, United States, 72205
    • California
      • Covina, California, United States, 91723
      • Escondido, California, United States, 92025
      • Fullerton, California, United States, 92835
      • Huntington Beach, California, United States, 92646
      • La Jolla, California, United States, 92037
      • Lakewood, California, United States, 90712
      • Long Beach, California, United States, 90808
      • Los Angeles, California, United States, 90048
      • Murrieta, California, United States, 92563
      • Newport Beach, California, United States, 92663
      • Pasadena, California, United States, 91107
      • Sacramento, California, United States, 95825
      • San Diego, California, United States, 92108
      • San Leandro, California, United States, 94578
      • Santa Barbara, California, United States, 93108
      • Santa Maria, California, United States, 93454
      • Sherman Oaks, California, United States, 91423
      • Van Nuys, California, United States, 91405
      • Victorville, California, United States, 92295
      • Westlake Village, California, United States, 91361
      • Whittier, California, United States, 90606
    • Colorado
      • Colorado Springs, Colorado, United States, 80910
      • Denver, Colorado, United States, 80230
    • Connecticut
      • Bridgeport, Connecticut, United States, 06606
      • Danbury, Connecticut, United States, 06810
      • Hamden, Connecticut, United States, 06518
      • Trumbull, Connecticut, United States, 06611
    • Delaware
      • Lewes, Delaware, United States, 19958
    • Florida
      • Aventura, Florida, United States, 33180
      • Boca Raton, Florida, United States, 33486
      • Clearwater, Florida, United States, 33761
      • Dunedin, Florida, United States, 34698
      • Fort Lauderdale, Florida, United States, 33334
      • Gainesville, Florida, United States, 30501
      • Gainesville, Florida, United States, 32608
      • Jacksonville, Florida, United States, 32209
      • Lake Mary, Florida, United States, 32746
      • Melbourne, Florida, United States, 32901
      • Miami, Florida, United States, 33126
      • Miami, Florida, United States, 33133
      • Naples, Florida, United States, 34102
      • Ocala, Florida, United States, 34474
      • Orlando, Florida, United States, 32806
      • Palm Harbor, Florida, United States, 34684
      • Sarasota, Florida, United States, 34239
      • South Miami, Florida, United States, 33143
      • St. Petersburg, Florida, United States, 33710
      • Tampa, Florida, United States, 33614
      • Tampa, Florida, United States, 33618
    • Georgia
      • Atlanta, Georgia, United States, 30342
      • Gainesville, Georgia, United States, 30501
    • Idaho
      • Boise, Idaho, United States, 83702
      • Idaho Falls, Idaho, United States, 83404
      • Nampa, Idaho, United States, 83686
    • Illinois
      • Chicago, Illinois, United States, 60616
      • Maywood, Illinois, United States, 60153
      • Moline, Illinois, United States, 61265
      • Morton Grove, Illinois, United States, 60053
      • Peoria, Illinois, United States, 61602
      • Schaumburg, Illinois, United States, 60195
      • Springfield, Illinois, United States, 62704
      • Vernon Hills, Illinois, United States, 60061
    • Indiana
      • Evansville, Indiana, United States, 47714
      • Fort Wayne, Indiana, United States, 46804
      • South Bend, Indiana, United States, 46601
    • Iowa
      • Cedar Rapids, Iowa, United States, 52401
    • Kansas
      • Lees Summit, Kansas, United States, 64086
      • Wichita, Kansas, United States, 67208
    • Kentucky
      • Lexington, Kentucky, United States, 40515
    • Louisiana
      • Baton Rouge, Louisiana, United States, 70808
      • Baton Rouge, Louisiana, United States, 70810
      • Monroe, Louisiana, United States, 71203
      • New Orleans, Louisiana, United States, 70121
    • Maryland
      • Columbia, Maryland, United States, 21045
      • Ellicott City, Maryland, United States, 21042
      • Frederick, Maryland, United States, 21702
      • Wheaton, Maryland, United States, 20902
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
      • Fall River, Massachusetts, United States, 02720
      • Pascagoula, Massachusetts, United States, 39581
      • Peabody, Massachusetts, United States, 01960
      • Plymouth, Massachusetts, United States, 02360
      • Worcester, Massachusetts, United States, 01610
      • Worcester, Massachusetts, United States, 01605
    • Michigan
      • Battle Creek, Michigan, United States, 49015
      • Kalamazoo, Michigan, United States, 49048
      • Lansing, Michigan, United States, 48910
      • Petoskey, Michigan, United States, 49770
      • St Clair Shores, Michigan, United States, 48080
    • Minnesota
      • Duluth, Minnesota, United States, 55805
      • Eagan, Minnesota, United States, 55121
      • Edina, Minnesota, United States, 55435
      • St. Louis Park, Minnesota, United States, 55426
    • Mississippi
      • Flowood, Mississippi, United States, 39232
      • Hattiesburg, Mississippi, United States, 39402
      • Jackson, Mississippi, United States, 39202
      • Tupelo, Mississippi, United States, 38802
    • Missouri
      • Florissant, Missouri, United States, 63031
      • Saint Louis, Missouri, United States, 63117
      • Saint Louis, Missouri, United States, 63128
      • St Louis, Missouri, United States, 63110
      • St Louis, Missouri, United States, 63141
    • Montana
      • Kalispell, Montana, United States, 59901
    • Nebraska
      • Grand Island, Nebraska, United States, 68803
      • Lincoln, Nebraska, United States, 68516
    • Nevada
      • Reno, Nevada, United States, 89502
    • New Hampshire
      • Dover, New Hampshire, United States, 03820
      • Lebanon, New Hampshire, United States, 03756
    • New Jersey
      • Clifton, New Jersey, United States, 07012
      • Haddon Heights, New Jersey, United States, 08035
      • Manalapan, New Jersey, United States, 07726
      • Morristown, New Jersey, United States, 07962
      • New Brunswick, New Jersey, United States, 08903
      • Trenton, New Jersey, United States, 08360
      • Voorhees, New Jersey, United States, 08043
    • New Mexico
      • Las Cruces, New Mexico, United States, 88011
    • New York
      • Albany, New York, United States, 12206
      • Binghamton, New York, United States, 13905
      • Brooklyn, New York, United States, 11201
      • Cooperstown, New York, United States, 13326
      • Hewlett, New York, United States, 11557
      • Lake Success, New York, United States, 11042
      • New York, New York, United States, 10016
      • Olean, New York, United States, 14760
      • Orchard Park, New York, United States, 14127
      • Plainview, New York, United States, 11803
      • Rochester, New York, United States, 14618
      • Roslyn, New York, United States, 11576
      • Smithtown, New York, United States, 11787
      • Syracuse, New York, United States, 13210
      • Utica, New York, United States, 13504
    • North Carolina
      • Asheville, North Carolina, United States, 28803
      • Belmont, North Carolina, United States, 28012
      • Charlotte, North Carolina, United States, 28207
      • Charlotte, North Carolina, United States, 28204
      • Charlotte, North Carolina, United States, 28210
      • Durham, North Carolina, United States, 27704
      • Greenville, North Carolina, United States, 27834
      • Raleigh, North Carolina, United States, 27609
      • Rock Hill, North Carolina, United States, 29732
      • Wilmington, North Carolina, United States, 28401
    • North Dakota
      • Bismarck, North Dakota, United States, 58501
    • Ohio
      • Akron, Ohio, United States, 44333
      • Cincinnati, Ohio, United States, 45219
      • Cincinnati, Ohio, United States, 45255
      • Columbus, Ohio, United States, 43215
      • Columbus, Ohio, United States, 43210
      • Dayton, Ohio, United States, 45402
      • Gallipolis, Ohio, United States, 45631
      • Mayfield, Ohio, United States, 44143
      • Middleburg Heights, Ohio, United States, 44130
      • Perryburg, Ohio, United States, 43551
      • Zanesville, Ohio, United States, 43701
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73109
      • Oklahoma City, Oklahoma, United States, 73103
      • Tulsa, Oklahoma, United States, 74135
    • Oregon
      • Lake Oswego, Oregon, United States, 97035
    • Pennsylvania
      • Bethlehem, Pennsylvania, United States, 18015
      • Camp Hill, Pennsylvania, United States, 17011
      • Duncansville, Pennsylvania, United States, 16635
      • Lebanon, Pennsylvania, United States, 17042
      • Philadelphia, Pennsylvania, United States, 19152
      • Philadelphia, Pennsylvania, United States, 19141
      • Pottstown, Pennsylvania, United States, 19464
      • West Reading, Pennsylvania, United States, 19611
      • Wexford, Pennsylvania, United States, 15090
      • Willow Grove, Pennsylvania, United States, 19090
    • South Carolina
      • Charleston, South Carolina, United States, 29406
      • Columbia, South Carolina, United States, 29204
      • Hickory, South Carolina, United States, 28602
      • Myrtle Beach, South Carolina, United States, 29572
    • Tennessee
      • Hendersonville, Tennessee, United States, 37073
      • Hixson, Tennessee, United States, 37343
      • Jackson, Tennessee, United States, 38305
      • Knoxville, Tennessee, United States, 37909
      • Nashville, Tennessee, United States, 37027
    • Texas
      • Amarillo, Texas, United States, 79106
      • Amarillo, Texas, United States, 79124
      • Austin, Texas, United States, 78705
      • Austin, Texas, United States, 78749
      • Carrollton, Texas, United States, 75007
      • Dallas, Texas, United States, 75246
      • Dallas, Texas, United States, 75231
      • Dallas, Texas, United States, 75231-4406
      • Fort Worth, Texas, United States, 76107
      • Houston, Texas, United States, 77074
      • Houston, Texas, United States, 77090
      • Lubbock, Texas, United States, 79424
      • Mesquite, Texas, United States, 75150
      • Nassau Bay, Texas, United States, 77058
      • San Antonio, Texas, United States, 78229
      • San Antonio, Texas, United States, 78217
      • San Antonio, Texas, United States, 78258
      • Tyler, Texas, United States, 75701
      • Waco, Texas, United States, 76708
    • Vermont
      • Burlington, Vermont, United States, 05401
    • Virginia
      • Arlington, Virginia, United States, 22205
      • Burke, Virginia, United States, 22015
      • Richmond, Virginia, United States, 23294
      • Virginia Beach, Virginia, United States, 23454
    • Washington
      • Olympia, Washington, United States, 98502
      • Spokane, Washington, United States, 99204
      • Tacoma, Washington, United States, 98405
    • West Virginia
      • Beckley, West Virginia, United States, 25801
      • Clarksburg, West Virginia, United States, 26301
    • Wisconsin
      • Brookfield, Wisconsin, United States, 53045
      • Franklin, Wisconsin, United States, 53132
      • Glendale, Wisconsin, United States, 53217
      • Milwaukee, Wisconsin, United States, 53209
      • Onalaska, Wisconsin, United States, 54605

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • adult patients, >=18 years of age;
  • moderate to severe active rheumatoid arthritis for >6 months;
  • inadequate clinical response or unable to tolerate current or prior biologic or non-biologic Disease-modifying antirheumatic drug (DMARD) therapy;
  • Swollen joint count (SJC) >/=4 and Tender joint count (TJC) >/=4
  • body weight </=150kg
  • current permitted non-biologic DMARDs must be on stable dose for >/= 7 weeks prior to baseline;

Exclusion Criteria:

  • history of autoimmune disease or inflammatory joint disease other than rheumatoid arthritis;
  • functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in rheumatoid arthritis;
  • treatment with rituximab within 6 months before screening;
  • intraarticular corticosteroids within 8 weeks or intramuscular (im)/ intravenous (iv) corticosteroids within 12 weeks prior to screening;
  • known active current or history of recurrent infections, or any major episode of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tocilizumab 8 mg/kg Monotherapy
Participants received Tocilizumab 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion.
Drug: tocilizumab [RoActemra/Actemra]
8 mg/kg intravenous every 4 weeks for 24 weeks
Drug: tocilizumab [RoActemra/Actemra]
4 mg/kg every 4 weeks for 24 weeks
Experimental: Tocilizumab 4 mg/kg + DMARD
Participants received Tocilizumab (TCZ) 4 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants not achieving a 20% improvement from baseline in tender and swollen joint counts at Week 8 were to have their dosage increased to 8 mg/kg, per protocol. Beginning at Week 12 dosage increase to 8 mg/kg was at the discretion of the investigator. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion.
Drug: tocilizumab [RoActemra/Actemra]
8 mg/kg intravenous every 4 weeks for 24 weeks
Drug: tocilizumab [RoActemra/Actemra]
4 mg/kg every 4 weeks for 24 weeks
Drug: Nonbiologic DMARDs of investigator's choice
Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed
Experimental: Tocilizumab 8 mg/kg + DMARD
Participants received Tocilizumab (TCZ) 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase at the investigator's discretion.
Drug: tocilizumab [RoActemra/Actemra]
8 mg/kg intravenous every 4 weeks for 24 weeks
Drug: tocilizumab [RoActemra/Actemra]
4 mg/kg every 4 weeks for 24 weeks
Drug: Nonbiologic DMARDs of investigator's choice
Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period
Time Frame: 24 Weeks

An SAE was any adverse event that at any dose fulfilled at least one of the following criteria:

  • Was fatal (results in death)
  • Was life-threatening
  • Required in-patient hospitalization or prolongation of existing hospitalization
  • Resulted in persistent or significant disability/incapacity
  • Was a congenital anomaly/birth defect
  • Was medically significant or required intervention to prevent one or other of the outcomes listed above.
24 Weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Experiencing Serious Adverse Events of Special Interest
Time Frame: 24 Weeks

Serious Adverse Events of Special interest include:

  • Serious infections including opportunistic infections
  • Complications of diverticulitis (including lower gastrointestinal [GI] perforations)
  • Myocardial infarction/acute coronary syndrome
  • Stroke
  • Spontaneous or serious bleeding
  • Malignant neoplasms
24 Weeks
Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest
Time Frame: 24 Weeks

Non-serious adverse Events of Special interest include:

  • Serious/Medically Significant Hepatic Events
  • Spontaneous /Serious Bleeding
  • Malignant Neoplasms
24 Weeks
Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24
Time Frame: Weeks 8,16,24
Clinical Remission is defined as a Disease Activity Score 28 [DAS28] < 2.6. The DAS28 is a combined index for measuring disease activity in RA. The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Weeks 8,16,24
Change From Baseline in DAS28 Score at Weeks 8, 16 and 24
Time Frame: Baseline, Weeks 8,16,24

The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response C-reactive protein (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of < 2.6 represents clinical remission, a score of ≤ 3.2 represents low disease activity, and a score of > 5.1 represents high disease activity.

The Change from Baseline to Weeks 8, 16 and 24 is reported.
Baseline, Weeks 8,16,24
Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24
Time Frame: Baseline, Weeks 8,16,24

The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50%, and ≥70% improvement from baseline, respectively, in:

  1. Swollen Joint Count (66 joints) and Tender Joint Count (68 joints) and

  2. At least 3 of the following 5 assessments:

    • Patient's global assessment of pain-Visual Analog Scale (VAS)
    • Patient global assessment of disease activity-(VAS)
    • Physician global assessment of disease activity-(VAS)
    • Patient assessment of disability (physical function scale of the Multidimensional Health Assessment Questionnaire)
    • Acute phase response C-Reactive Protein (CRP)
Baseline, Weeks 8,16,24
Percentage of Participants With Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Week 8
Time Frame: Baseline, Week 8
Dosage could be increased from 4 mg/kg Tocilizumab to 8 mg/kg due to failure to achieve 20% improvement from baseline in swollen and tender joint counts.
Baseline, Week 8
Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20
Time Frame: Weeks 12,16, 20
Dosage of Tocilizumab 4 mg/kg could be increased to 8 mg/kg at the discretion of the investigator based on assessment of the patient's benefit-risk after Week 12.
Weeks 12,16, 20
Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24
Time Frame: Baseline, Weeks 8,16,24
The RAPID3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain Visual Analog Scale (VAS), and global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 10 where higher scores represent worse outcomes. A negative change from baseline indicates improvement.
Baseline, Weeks 8,16,24
Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24
Time Frame: Baseline, Weeks 8,16,24
The fatigue VAS is a single-item, patient-reported outcome that measures the severity of the fatigue over the past week. Patients rate their fatigue on a scale of 0 (fatigue is no problem) to 100 (fatigue is a major problem). Higher scores represent higher disease activity and a negative change from baseline indicates improvement.
Baseline, Weeks 8,16,24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hoffmann-La Roche

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2009

Primary Completion (Actual)

July 1, 2010

Study Completion (Actual)

March 1, 2011

Study Registration Dates

First Submitted

April 29, 2009

First Submitted That Met QC Criteria

April 29, 2009

First Posted (Estimate)

April 30, 2009

Study Record Updates

Last Update Posted (Estimate)

October 25, 2012

Last Update Submitted That Met QC Criteria

October 19, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ML22533

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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