A Study of the Impact of Methotrexate (MTX) Discontinuation on the Efficacy of Subcutaneous (SC) Tocilizumab (TCZ) With MTX

Rheumatoid Arthritis Clinical Trial

Official title:

A Randomized, Double-Blind Trial Assessing the Impact of Methotrexate Discontinuation on the Efficacy of Subcutaneous Tocilizumab With Methotrexate Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01855789
• Other study ID #: ML28776
• Status: Completed
• Phase: Phase 3
• First received: May 14, 2013
• Last updated: November 30, 2017
• Start date: November 7, 2013
• Est. completion date: October 14, 2016

Study information

• Verified date: November 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 718
• Est. completion date: October 14, 2016
• Est. primary completion date: October 14, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Tocilizumab (TCZ)
TCZ will be administered at a dose of 162 milligrams (mg) via SC injection weekly (if body weight is greater than or equal to [>/=] 100 kilograms [kg]) or every 2 weeks (if body weight was less than [<] 100 kg).
• Methotrexate (MTX)
MTX will be administered at a stable dose (15 mg to 25 mg per week) orally.
• Placebo (PBO)
PBO matching to MTX will be administered orally.

Locations

Country	Name	City	State
United States	Crystal Arthritis Center, Inc.	Akron	Ohio
United States	The Center for Rheumatology	Albany	New York
United States	Albuquerque Clinical Trials	Albuquerque	New Mexico
United States	Amarillo Center For Clinical Research	Amarillo	Texas
United States	Pinnacle Research Group; Llc, Central	Anniston	Alabama
United States	Arthritis Care Center Oklahoma	Ardmore	Oklahoma
United States	Asheville Arthritis & Osteoporosis Center, PA	Asheville	North Carolina
United States	University of Colorado Hospital	Aurora	Colorado
United States	Austin Regional Clinic	Austin	Texas
United States	Lovelace Scientific Resources Inc.	Austin	Texas
United States	Arthritis & Rheumatism; Disease Specialities	Aventura	Florida
United States	Diagnostic Group	Beaumont	Texas
United States	Uni Of Alabama,Birmingham; Medicine - Rheumatology	Birmingham	Alabama
United States	Odyssey Research Services; Main Medical Building	Bismarck	North Dakota
United States	St. Alexius Medical Center; Arthritis Clinic	Bismarck	North Dakota
United States	New England Medical Center; Dept. of Medicine, Div. of Rheumatology	Boston	Massachusetts
United States	Joao Nascimento	Bridgeport	Connecticut
United States	Arthritis & Osteoporosis Center	Brooklyn	New York
United States	Low Country Rheumatology, PA	Charleston	South Carolina
United States	Carolina Bone & Joint P.A.	Charlotte	North Carolina
United States	Cincinnati Rheumatic Disease Study Group	Cincinnati	Ohio
United States	Mountain State Clinical Research	Clarksburg	West Virginia
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	AOCBV	College Station	Texas
United States	Arthritis Assoc & Osteoporosis; Ctr of Colorado Springs	Colorado Springs	Colorado
United States	Columbia Arthritis Center (Partnership Practice)	Columbia	South Carolina
United States	Columbus Arthritis Center	Columbus	Ohio
United States	Ohio State University; Rheumatology; Immun/Rheum	Columbus	Ohio
United States	Adriana Pop-Moody MD Clinic PA	Corpus Christi	Texas
United States	Medvin Clinical Research	Covina	California
United States	Arthritis Care & Diagnostic Center	Dallas	Texas
United States	Metroplex Clinical Research	Dallas	Texas
United States	Clinical Research Center of Ct/Ny	Danbury	Connecticut
United States	STAT Research Inc	Dayton	Ohio
United States	Denver Arthritis Clinic	Denver	Colorado
United States	North Georgia Rheumatology	Duluth	Georgia
United States	St. Luke's Hospital Association of Duluth	Duluth	Minnesota
United States	Altoona Center For Clinical Research	Duncansville	Pennsylvania
United States	Robert Levin, Md; Research Dept	Dunedin	Florida
United States	Triangle Orthopaedics Associates, P.A.	Durham	North Carolina
United States	St. Paul Rheumatology	Eagan	Minnesota
United States	TriWest Research Associates, LLC	El Cajon	California
United States	Arthritis Associates	Erie	Pennsylvania
United States	Phase Iii Clinical Research	Fall River	Massachusetts
United States	David S Rosenberg	Florissant	Missouri
United States	Arthritis and Osteoporosis; Treatment and Research Center	Flowood	Mississippi
United States	Jackson Arthritis Clinic	Flowood	Mississippi
United States	Fort Smith Rheumatology, PC	Fort Smith	Arkansas
United States	St. Jude Hospital Yorba Linda DBA St. Joseph	Fullerton	California
United States	Arthritis Center of North Georgia	Gainesville	Georgia
United States	Arizona Arthritis & Rheumatology Associates, P.C.	Glendale	Arizona
United States	Rheumatic Disease Center	Glendale	Wisconsin
United States	Medication Management	Greensboro	North Carolina
United States	Piedmont Arthritis Clinic	Greenville	South Carolina
United States	Klein & Associates, M.D., P.A.	Hagerstown	Maryland
United States	Arthritis & Osteoporosis Center Pc	Hamden	Connecticut
United States	CV Mehta MD Medical Corp	Hemet	California
United States	PMG Research of Hickory LLC	Hickory	North Carolina
United States	CHI St. Vincent Medical Group Hot Springs	Hot Springs	Arkansas
United States	Accurate Clinical Research	Houston	Texas
United States	Houston Inst. For Clinical Research	Houston	Texas
United States	IntraFusion Researh Network	Houston	Texas
United States	Rheumatic Disease Clin Res Ctr	Houston	Texas
United States	Rheumatology Associates of North Alabama	Huntsville	Alabama
United States	Institute of Arthritis Research	Idaho Falls	Idaho
United States	Diagnostic Rheumatology & Research	Indianapolis	Indiana
United States	Indiana Uni Medical Center	Indianapolis	Indiana
United States	West Tennessee Research Institute	Jackson	Tennessee
United States	NEA Baptist Clinic	Jonesboro	Arkansas
United States	Clinical Research Consultants,LLC	Kansas City	Missouri
United States	Advanced Rheumatology, PC	Lansing	Michigan
United States	Fiechtner Research Inc	Lansing	Michigan
United States	Arthritis and Osteoporosis Associates of New Mexico	Las Cruces	New Mexico
United States	G. T. Kelly, MD	Las Vegas	Nevada
United States	North Georgia Rheumatology Group, PC	Lawrenceville	Georgia
United States	Rheumatology Research Group	Lebanon	New Hampshire
United States	Cape Fear Arthritis Care	Leland	North Carolina
United States	Rheumatolgy Consultants of Deleware	Lewes	Delaware
United States	Bluegrass Comm Research, Inc.	Lexington	Kentucky
United States	Little Rock Diagnostic Clinic	Little Rock	Arkansas
United States	Valerius Medical Group	Los Alamitos	California
United States	Arthritis and Osteoporosis Associates	Manalapan	New Jersey
United States	Manhasset Rheumatology	Manhasset	New York
United States	Lakeshore Orthopedics	Manitowoc	Wisconsin
United States	Mansfield Medical Center	Mansfield	Massachusetts
United States	Ramesh Gupta - PP	Memphis	Tennessee
United States	Arizona Arthritis & Rheumatology Research, Pllc	Mesa	Arizona
United States	Arizona Arthritis and Rheuma	Mesa	Arizona
United States	Southwest Rheumatology	Mesquite	Texas
United States	South Coast Research Center, Inc.	Miami	Florida
United States	Suncoast Research Group LLC	Miami	Florida
United States	Precision Research Organization	Miami Lakes	Florida
United States	Paramount Medical Research	Middleburg Heights	Ohio
United States	Arthritis & Diabetes Clinic, Inc	Monroe	Louisiana
United States	Jeffrey Alper M.D Research	Naples	Florida
United States	Nashua Rheumatology - Foundation Medical Partners	Nashua	New Hampshire
United States	Manhattan Medical Reserach	New York	New York
United States	Javed Rheumatology Associates, Inc.	Newark	Delaware
United States	Arthritis and Rheumatology; Center of Oklahoma PLLC	Oklahoma City	Oklahoma
United States	Health Research of Oklahoma, Llc	Oklahoma City	Oklahoma
United States	Lynn Health Science Inst.	Oklahoma City	Oklahoma
United States	South Puget Sound Clinical Research	Olympia	Washington
United States	Gundersen Clinic Ltd;Sec. Rheumatology/Dept. of Internal Med	Onalaska	Wisconsin
United States	NRC Research Institute	Orange	California
United States	Buffalo Rheumatology Associates	Orchard Park	New York
United States	Arthritis and Rheumatology Clinic	Orlando	Florida
United States	Rheumatology Associates of Central Florida	Orlando	Florida
United States	Kansas City Internal Medicine	Overland Park	Kansas
United States	Arthritis Center Palm Harbor	Palm Harbor	Florida
United States	Arthritis Rsrch of Florida, Inc.	Palm Harbor	Florida
United States	Nisus Research/Northern Michigan Hospital	Petoskey	Michigan
United States	Arthritis Group	Philadelphia	Pennsylvania
United States	Valley Arthritis Care	Phoenix	Arizona
United States	Office of Premier Chatpar Md	Plainview	New York
United States	Shanahan Rheumatology & Immunology, PLLC	Raleigh	North Carolina
United States	Shores Rheumatology	Saint Clair Shores	Michigan
United States	Arthritis Consultants	Saint Louis	Missouri
United States	Clayton Medical Research	Saint Louis	Missouri
United States	Pinellas Medical Research - Allegry & Rheumatology Associates, LLC	Saint Petersburg	Florida
United States	Accurate Clinical Management	San Antonio	Texas
United States	Arthiritis & Osteoporosis Centre of South Texas	San Antonio	Texas
United States	NextGen Clinical Research Inc	San Antonio	Texas
United States	San Diego Arthritis Med Clnc	San Diego	California
United States	C Michael Neuwelt MD Inc	San Leandro	California
United States	Arthritis Clinic Of Central Texas	San Marcos	Texas
United States	Sarasota Arthritis Res Center	Sarasota	Florida
United States	Advanced Arthritis Care & Research	Scottsdale	Arizona
United States	Rheumatology Associates of Long Island	Smithtown	New York
United States	Arthritis Northwest, Spokane	Spokane	Washington
United States	Springfield Clinic	Springfield	Illinois
United States	Arthritis Health Associates	Syracuse	New York
United States	West Broward Rheumatology Associates, Inc.	Tamarac	Florida
United States	Burnette & Silverfield, MDS	Tampa	Florida
United States	McIlwain Medical Group	Tampa	Florida
United States	Clinical Research Source, Inc.	Toledo	Ohio
United States	Atlantic Coast Rheumatology	Toms River	New Jersey
United States	Ocean Rheumatology	Toms River	New Jersey
United States	New England Research Associates	Trumbull	Connecticut
United States	Healthcare Research Consultants	Tulsa	Oklahoma
United States	Oklahoma Center For Arthritis Therapy & Research	Tulsa	Oklahoma
United States	Clnical & Translational Reseach Center for Alabama, PC	Tuscaloosa	Alabama
United States	Inland Rheumatology; Clinical Trials, Inc.	Upland	California
United States	Crossroads Clinical Research, LLC	Victoria	Texas
United States	Arthritis Rheumatic & Back Disease Associates	Voorhees	New Jersey
United States	Cooper Cancer Institute	Voorhees	New Jersey
United States	Arthritis & Osteoporosis Clinic	Waco	Texas
United States	Wenatchee Valley Hospital & Clinics	Wenatchee	Washington
United States	Advanced Rheumatology & Arthritis Research Center	Wexford	Pennsylvania
United States	Medvin Clinical Research	Whittier	California
United States	Advanced Clinical Research of Orlando, Inc.	Winter Garden	Florida
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts
United States	Reliant Medical Group, Inc; Rheumatology	Worcester	Massachusetts
United States	UMass Memorial Medical Center	Worcester	Massachusetts
United States	Clinical Research Center of Reading	Wyomissing	Pennsylvania
United States	Emkey Arthritis & Osteoporosis	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40	The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity.	Week 24, Week 40
Secondary	Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response	The ACR20 response at any time was defined as >/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein [CRP] in milligrams per deciliter [mg/dL]).	Weeks 24, 40, and 52
Secondary	Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response	The ACR50 response at any time was defined as >/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).	Weeks 24, 40, and 52
Secondary	Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response	The ACR70 response at any time was defined as >/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).	Weeks 24, 40, and 52
Secondary	Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52	The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28- score could range from 0 to 10, where higher score represented higher disease activity.	Week 24, 40, and 52
Secondary	Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission)	The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity.	Week 40, Week 52
Secondary	Percentage of Participants With DAS28 Score </=3.2 (Low DAS28)	The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28-ESR score could range from 0 to 10, where higher score represented higher disease activity.	Week 40, Week 52
Secondary	Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy	Bones from the wrist regions (carpal bones, distal radius, distal ulna, and metacarpal bases) and the metacarpophalangeal (MCP) joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranged from 0 (no erosion) to 10 (91-100%). Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value for change from Week 24 in bone erosion score indicated an improvement.	Weeks 24, Week 40
Secondary	Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ	Percentage of participants with positive results for ATA against TCZ at Baseline and at any of the post-baseline assessment time-points was reported. Participants positive at any post-baseline time points were participants who had no positivity at baseline for the same assay.	Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60])
Secondary	Mean TCZ Serum Concentration		Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)
Secondary	Mean Soluble Interleukin-6 (IL-6) Receptor Concentration		Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)