Clinical trial NCT01855789: A Study of the Impact of Methotrexate (MTX) Discontinuation on the Efficacy of Subcutaneous (SC) Tocilizumab (TCZ) With MTX
Official title: A Randomized, Double-Blind Trial Assessing the Impact of Methotrexate Discontinuation on the Efficacy of Subcutaneous Tocilizumab With Methotrexate Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-05-17
Enrollment: 718
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized, multicenter, double-blind, parallel group study will evaluate the impact of MTX discontinuation on the efficacy of SC TCZ in participants with moderate to severe active rheumatoid arthritis who have an inadequate response to current MTX therapy. Participants will initiate treatment with TCZ weekly or every 2 weeks along with MTX at a stable dose orally in an open-label manner for 24 weeks. Participants with a disease activity score based on 28 joints (DAS28) less than or equal to (\</=) 3.2 at Week 24, will be randomized to either continue receiving a stable dose of MTX or to switch to matching placebo up to Week 52. Participants without a DAS28 score \</=3.2 at Week 24, will continue the same treatment in a non-randomized open-label manner up to Week 52.


Eligibility criteria: Inclusion Criteria:

* Body weight \</=150 kg
* Active moderate to severe rheumatoid arthritis (DAS28 \>/=4.4) according to the revised 1987 ACR criteria at screening and baseline (prior to treatment on Day 1)
* Currently receiving oral MTX for at least 24 weeks and on a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1), with the following exception: a stable dose of at least 10 mg/week is allowed for participants with a body weight \<50 kg or calculated glomerular filtration rate (or creatinine clearance) \<60 milliliters per minute (mL/min)
* History of parenteral (SC or intramuscular \[IM\]) MTX is allowed, but not within 6 weeks prior to treatment (Day 1). Participants must not have a documented, clinically significant intolerance to oral MTX and must be receiving oral MTX at a dose of 15 mg/week for at least 6 weeks prior to treatment (Day 1)
* Participants who have received one prior anti-tumor necrosis factor (TNF) must have discontinued etanercept, infliximab, certolizumab, adalimumab, or golimumab for at least 6 months prior to screening
* Oral corticosteroids must have been \</=10 mg/day prednisone (or equivalent) and stable for at least 25 out of 28 days prior to treatment (Day 1)
* Participants receiving treatment on an outpatient basis

Exclusion Criteria:

* Documented medical history of significant intolerance to oral MTX \>/=15 mg/week
* Participants receiving other (non-MTX) disease modifying anti-rheumatic drugs (DMARDs) within 8 weeks of screening
* Previous treatment with abatacept, rituximab, tofacitinib, or anakinra
* Treatment with parenteral corticosteroids within 4 weeks prior to treatment
* Previous treatment with cell-depleting therapies or alkylating agents
* Previous treatment with TCZ
* Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery during the study
* Rheumatic autoimmune disease other than rheumatoid arthritis
* Non-rheumatic active autoimmune diseases (for example, inflammatory bowel diseases, psoriasis, multiple sclerosis)
* Prior history of or current inflammatory joint disease other than rheumatoid arthritis
* Functional Class IV according to the revised (1987) ACR criteria for rheumatoid arthritis
* History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
* Evidence of significant uncontrolled concomitant diseases; uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids
* Active current or history of recurrent infection, or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening
* Active tuberculosis requiring treatment within the previous 3 years
* History of or currently active primary or secondary immunodeficiency
* Pregnant or breast-feeding women
* Positive for hepatitis B or hepatitis C infection
* For potential MRI substudy participants: the presence of any metal-containing device or object in the body

Primary outcomes:
measure: Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40
timeFrame: Week 24, Week 40
Secondary outcomes:
measure: Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response
timeFrame: Weeks 24, 40, and 52
measure: Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response
timeFrame: Weeks 24, 40, and 52
measure: Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response
timeFrame: Weeks 24, 40, and 52
measure: Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52
timeFrame: Week 24, 40, and 52
measure: Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission)
timeFrame: Week 40, Week 52
measure: Percentage of Participants With DAS28 Score </=3.2 (Low DAS28)
timeFrame: Week 40, Week 52
measure: Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy
timeFrame: Weeks 24, Week 40
measure: Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ
timeFrame: Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60])
measure: Mean TCZ Serum Concentration
timeFrame: Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)
measure: Mean Soluble Interleukin-6 (IL-6) Receptor Concentration
timeFrame: Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group; Llc, Central
state: Alabama
city: Birmingham
country: United States
facility: Uni Of Alabama,Birmingham; Medicine - Rheumatology
state: Alabama
city: Huntsville
country: United States
facility: Rheumatology Associates of North Alabama
state: Alabama
city: Tuscaloosa
country: United States
facility: Clnical & Translational Reseach Center for Alabama, PC
state: Alabama
city: Glendale
country: United States
facility: Arizona Arthritis & Rheumatology Associates, P.C.
state: Arizona
city: Mesa
country: United States
facility: Arizona Arthritis & Rheumatology Research, Pllc
state: Arizona
city: Mesa
country: United States
facility: Arizona Arthritis and Rheuma
state: Arizona
city: Phoenix
country: United States
facility: Valley Arthritis Care
state: Arizona
city: Scottsdale
country: United States
facility: Advanced Arthritis Care & Research
state: Arizona
city: Fort Smith
country: United States
facility: Fort Smith Rheumatology, PC
state: Arkansas
city: Hot Springs
country: United States
facility: CHI St. Vincent Medical Group Hot Springs
state: Arkansas
city: Jonesboro
country: United States
facility: NEA Baptist Clinic
state: Arkansas
city: Little Rock
country: United States
facility: Little Rock Diagnostic Clinic
state: Arkansas
city: Covina
country: United States
facility: Medvin Clinical Research
state: California
city: El Cajon
country: United States
facility: TriWest Research Associates, LLC
state: California
city: Fullerton
country: United States
facility: St. Jude Hospital Yorba Linda DBA St. Joseph
state: California
city: Hemet
country: United States
facility: CV Mehta MD Medical Corp
state: California
city: Los Alamitos
country: United States
facility: Valerius Medical Group
state: California
city: Orange
country: United States
facility: NRC Research Institute
state: California
city: San Diego
country: United States
facility: San Diego Arthritis Med Clnc
state: California
city: San Leandro
country: United States
facility: C Michael Neuwelt MD Inc
state: California
city: Upland
country: United States
facility: Inland Rheumatology; Clinical Trials, Inc.
state: California
city: Whittier
country: United States
facility: Medvin Clinical Research
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Colorado Springs
country: United States
facility: Arthritis Assoc & Osteoporosis; Ctr of Colorado Springs
state: Colorado
city: Denver
country: United States
facility: Denver Arthritis Clinic
state: Colorado
city: Bridgeport
country: United States
facility: Joao Nascimento
state: Connecticut
city: Danbury
country: United States
facility: Clinical Research Center of Ct/Ny
state: Connecticut
city: Hamden
country: United States
facility: Arthritis & Osteoporosis Center Pc
state: Connecticut
city: Trumbull
country: United States
facility: New England Research Associates
state: Connecticut
city: Lewes
country: United States
facility: Rheumatolgy Consultants of Deleware
state: Delaware
city: Newark
country: United States
facility: Javed Rheumatology Associates, Inc.
state: Delaware
city: Aventura
country: United States
facility: Arthritis & Rheumatism; Disease Specialities
state: Florida
city: Dunedin
country: United States
facility: Robert Levin, Md; Research Dept
state: Florida
city: Miami Lakes
country: United States
facility: Precision Research Organization
state: Florida
city: Miami
country: United States
facility: Suncoast Research Group LLC
state: Florida
city: Miami
country: United States
facility: South Coast Research Center, Inc.
state: Florida
city: Naples
country: United States
facility: Jeffrey Alper M.D Research
state: Florida
city: Orlando
country: United States
facility: Rheumatology Associates of Central Florida
state: Florida
city: Orlando
country: United States
facility: Arthritis and Rheumatology Clinic
state: Florida
city: Palm Harbor
country: United States
facility: Arthritis Center Palm Harbor
state: Florida
city: Palm Harbor
country: United States
facility: Arthritis Rsrch of Florida, Inc.
state: Florida
city: Saint Petersburg
country: United States
facility: Pinellas Medical Research - Allegry & Rheumatology Associates, LLC
state: Florida
city: Sarasota
country: United States
facility: Sarasota Arthritis Res Center
state: Florida
city: Tamarac
country: United States
facility: West Broward Rheumatology Associates, Inc.
state: Florida
city: Tampa
country: United States
facility: McIlwain Medical Group
state: Florida
city: Tampa
country: United States
facility: Burnette & Silverfield, MDS
state: Florida
city: Winter Garden
country: United States
facility: Advanced Clinical Research of Orlando, Inc.
state: Florida
city: Duluth
country: United States
facility: North Georgia Rheumatology
state: Georgia
city: Gainesville
country: United States
facility: Arthritis Center of North Georgia
state: Georgia
city: Lawrenceville
country: United States
facility: North Georgia Rheumatology Group, PC
state: Georgia
city: Idaho Falls
country: United States
facility: Institute of Arthritis Research
state: Idaho
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Uni Medical Center
state: Indiana
city: Indianapolis
country: United States
facility: Diagnostic Rheumatology & Research
state: Indiana
city: Overland Park
country: United States
facility: Kansas City Internal Medicine
state: Kansas
city: Lexington
country: United States
facility: Bluegrass Comm Research, Inc.
state: Kentucky
city: Monroe
country: United States
facility: Arthritis & Diabetes Clinic, Inc
state: Louisiana
city: Hagerstown
country: United States
facility: Klein & Associates, M.D., P.A.
state: Maryland
city: Boston
country: United States
facility: New England Medical Center; Dept. of Medicine, Div. of Rheumatology
state: Massachusetts
city: Fall River
country: United States
facility: Phase Iii Clinical Research
state: Massachusetts
city: Mansfield
country: United States
facility: Mansfield Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: Reliant Medical Group, Inc; Rheumatology
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: Clinical Pharmacology Study Group
state: Massachusetts
city: Lansing
country: United States
facility: Advanced Rheumatology, PC
state: Michigan
city: Lansing
country: United States
facility: Fiechtner Research Inc
state: Michigan
city: Petoskey
country: United States
facility: Nisus Research/Northern Michigan Hospital
state: Michigan
city: Saint Clair Shores
country: United States
facility: Shores Rheumatology
state: Michigan
city: Duluth
country: United States
facility: St. Luke's Hospital Association of Duluth
state: Minnesota
city: Eagan
country: United States
facility: St. Paul Rheumatology
state: Minnesota
city: Flowood
country: United States
facility: Arthritis and Osteoporosis; Treatment and Research Center
state: Mississippi
city: Flowood
country: United States
facility: Jackson Arthritis Clinic
state: Mississippi
city: Florissant
country: United States
facility: David S Rosenberg
state: Missouri
city: Kansas City
country: United States
facility: Clinical Research Consultants,LLC
state: Missouri
city: Saint Louis
country: United States
facility: Clayton Medical Research
state: Missouri
city: Saint Louis
country: United States
facility: Arthritis Consultants
state: Missouri
city: Las Vegas
country: United States
facility: G. T. Kelly, MD
state: Nevada
city: Lebanon
country: United States
facility: Rheumatology Research Group
state: New Hampshire
city: Nashua
country: United States
facility: Nashua Rheumatology - Foundation Medical Partners
state: New Hampshire
city: Manalapan
country: United States
facility: Arthritis and Osteoporosis Associates
state: New Jersey
city: Toms River
country: United States
facility: Atlantic Coast Rheumatology
state: New Jersey
city: Toms River
country: United States
facility: Ocean Rheumatology
state: New Jersey
city: Voorhees
country: United States
facility: Arthritis Rheumatic & Back Disease Associates
state: New Jersey
city: Voorhees
country: United States
facility: Cooper Cancer Institute
state: New Jersey
city: Albuquerque
country: United States
facility: Albuquerque Clinical Trials
state: New Mexico
city: Las Cruces
country: United States
facility: Arthritis and Osteoporosis Associates of New Mexico
state: New Mexico
city: Albany
country: United States
facility: The Center for Rheumatology
state: New York
city: Brooklyn
country: United States
facility: Arthritis & Osteoporosis Center
state: New York
city: Manhasset
country: United States
facility: Manhasset Rheumatology
state: New York
city: New York
country: United States
facility: Manhattan Medical Reserach
state: New York
city: Orchard Park
country: United States
facility: Buffalo Rheumatology Associates
state: New York
city: Plainview
country: United States
facility: Office of Premier Chatpar Md
state: New York
city: Smithtown
country: United States
facility: Rheumatology Associates of Long Island
state: New York
city: Syracuse
country: United States
facility: Arthritis Health Associates
state: New York
city: Asheville
country: United States
facility: Asheville Arthritis & Osteoporosis Center, PA
state: North Carolina
city: Charlotte
country: United States
facility: Carolina Bone & Joint P.A.
state: North Carolina
city: Durham
country: United States
facility: Triangle Orthopaedics Associates, P.A.
state: North Carolina
city: Greensboro
country: United States
facility: Medication Management
state: North Carolina
city: Hickory
country: United States
facility: PMG Research of Hickory LLC
state: North Carolina
city: Leland
country: United States
facility: Cape Fear Arthritis Care
state: North Carolina
city: Raleigh
country: United States
facility: Shanahan Rheumatology & Immunology, PLLC
state: North Carolina
city: Bismarck
country: United States
facility: St. Alexius Medical Center; Arthritis Clinic
state: North Dakota
city: Bismarck
country: United States
facility: Odyssey Research Services; Main Medical Building
state: North Dakota
city: Akron
country: United States
facility: Crystal Arthritis Center, Inc.
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Rheumatic Disease Study Group
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University; Rheumatology; Immun/Rheum
state: Ohio
city: Columbus
country: United States
facility: Columbus Arthritis Center
state: Ohio
city: Dayton
country: United States
facility: STAT Research Inc
state: Ohio
city: Middleburg Heights
country: United States
facility: Paramount Medical Research
state: Ohio
city: Toledo
country: United States
facility: Clinical Research Source, Inc.
state: Ohio
city: Ardmore
country: United States
facility: Arthritis Care Center Oklahoma
state: Oklahoma
city: Oklahoma City
country: United States
facility: Arthritis and Rheumatology; Center of Oklahoma PLLC
state: Oklahoma
city: Oklahoma City
country: United States
facility: Health Research of Oklahoma, Llc
state: Oklahoma
city: Oklahoma City
country: United States
facility: Lynn Health Science Inst.
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Center For Arthritis Therapy & Research
state: Oklahoma
city: Tulsa
country: United States
facility: Healthcare Research Consultants
state: Oklahoma
city: Duncansville
country: United States
facility: Altoona Center For Clinical Research
state: Pennsylvania
city: Erie
country: United States
facility: Arthritis Associates
state: Pennsylvania
city: Philadelphia
country: United States
facility: Arthritis Group
state: Pennsylvania
city: Wexford
country: United States
facility: Advanced Rheumatology & Arthritis Research Center
state: Pennsylvania
city: Wyomissing
country: United States
facility: Clinical Research Center of Reading
state: Pennsylvania
city: Wyomissing
country: United States
facility: Emkey Arthritis & Osteoporosis
state: Pennsylvania
city: Charleston
country: United States
facility: Low Country Rheumatology, PA
state: South Carolina
city: Columbia
country: United States
facility: Columbia Arthritis Center (Partnership Practice)
state: South Carolina
city: Greenville
country: United States
facility: Piedmont Arthritis Clinic
state: South Carolina
city: Jackson
country: United States
facility: West Tennessee Research Institute
state: Tennessee
city: Memphis
country: United States
facility: Ramesh Gupta - PP
state: Tennessee
city: Amarillo
country: United States
facility: Amarillo Center For Clinical Research
state: Texas
city: Austin
country: United States
facility: Austin Regional Clinic
state: Texas
city: Austin
country: United States
facility: Lovelace Scientific Resources Inc.
state: Texas
city: Beaumont
country: United States
facility: Diagnostic Group
state: Texas
city: College Station
country: United States
facility: AOCBV
state: Texas
city: Corpus Christi
country: United States
facility: Adriana Pop-Moody MD Clinic PA
state: Texas
city: Dallas
country: United States
facility: Arthritis Care & Diagnostic Center
state: Texas
city: Dallas
country: United States
facility: Metroplex Clinical Research
state: Texas
city: Houston
country: United States
facility: Rheumatic Disease Clin Res Ctr
state: Texas
city: Houston
country: United States
facility: IntraFusion Researh Network
state: Texas
city: Houston
country: United States
facility: Houston Inst. For Clinical Research
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Research
state: Texas
city: Mesquite
country: United States
facility: Southwest Rheumatology
state: Texas
city: San Antonio
country: United States
facility: Accurate Clinical Management
state: Texas
city: San Antonio
country: United States
facility: NextGen Clinical Research Inc
state: Texas
city: San Antonio
country: United States
facility: Arthiritis & Osteoporosis Centre of South Texas
state: Texas
city: San Marcos
country: United States
facility: Arthritis Clinic Of Central Texas
state: Texas
city: Victoria
country: United States
facility: Crossroads Clinical Research, LLC
state: Texas
city: Waco
country: United States
facility: Arthritis & Osteoporosis Clinic
state: Texas
city: Olympia
country: United States
facility: South Puget Sound Clinical Research
state: Washington
city: Spokane
country: United States
facility: Arthritis Northwest, Spokane
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Hospital & Clinics
state: Washington
city: Clarksburg
country: United States
facility: Mountain State Clinical Research
state: West Virginia
city: Glendale
country: United States
facility: Rheumatic Disease Center
state: Wisconsin
city: Manitowoc
country: United States
facility: Lakeshore Orthopedics
state: Wisconsin
city: Onalaska
country: United States
facility: Gundersen Clinic Ltd;Sec. Rheumatology/Dept. of Internal Med
state: Wisconsin
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, Pei J, Michalska M. Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial. Arthritis Rheumatol. 2018 Aug;70(8):1200-1208. doi: 10.1002/art.40493. Epub 2018 Jun 14.