Clinical trial NCT00106535: A Study to Assess the Effect of Tocilizumab + Methotrexate on Prevention of Structural Joint Damage in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)
Official title: A Randomized, Double-blind Study of Safety and Prevention of Structural Joint Damage During Treatment With Tocilizumab Versus Placebo, in Combination With Methotrexate, in Patients With Moderate to Severe Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2005-03-28
Enrollment: 1196
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 3 arm study will compare the safety and efficacy, with respect to a reduction in signs and symptoms and prevention of joint damage, of tocilizumab versus placebo, both in combination with methotrexate (MTX) in patients with moderate to severe active rheumatoid arthritis. Patients will be randomized to receive tocilizumab 4 mg/kg IV, tocilizumab 8 mg/kg IV or placebo IV, every 4 weeks. All patients will also receive methotrexate, 10-25 mg/week. The anticipated time on study treatment is 1-2 years and the target sample size is 500+ individuals. After completion of the 2 year study participants could participate in the optional 3 year open label extension phase (year 3 to 5).


Eligibility criteria: Inclusion Criteria:

* adult patients at least 18 years of age with moderate to severe active RA for at least 6 months;
* inadequate response to a stable dose of MTX;
* patients of reproductive potential must be using reliable methods of contraception.

Exclusion Criteria:

* major surgery (including joint surgery) within 8 weeks before entering study, or planned surgery within 6 months after entering study;
* prior treatment failure with an anti-tumor necrosis factor agent;
* women who are pregnant or breast-feeding.

Primary outcomes:
measure: Percentage of Participants With American College of Rheumatology-ACR20 Response
timeFrame: Baseline, Week 24
measure: Change From Baseline in Modified Total Sharp-Genant Score at Week 52
timeFrame: Baseline, Week 52
measure: Change in Physical Function as Measured by the Area Under the Curve (AUC) for the Change From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in the Modified Total Sharp-Genant Score at Week 104
timeFrame: Baseline, Week 104
measure: Change in Physical Function as Measured by the Area Under the Curve for the Change From Baseline in the Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 104
timeFrame: Baseline to Week 104
Secondary outcomes:
measure: Percentage of Participants With ACR50 Response
timeFrame: Baseline, Week 24
measure: Percentage of Participants With ACR70 Response
timeFrame: Baseline,Week 24
measure: Swollen Joint Count (66 Joint Count): Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Tender Joint Count (68 Joint Count): Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Patient's Global Visual Analog Scale (VAS): Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Physician's Global VAS: Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Patient's Pain VAS: Mean Change From Baseline at Week 24
timeFrame: Baseline and Week 24
measure: C-Reactive Protein (CRP): Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Erythrocyte Sedimentation Rate: Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Health Assessment Questionnaire Disability Index (HAQ-DI): Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With American College of Rheumatology (ACR20) Response at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants With ACR20 Response at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With ACR50 Response at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants With ACR50 Response at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With ACR70 Response at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants With ACR70 Response at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With ACR70 Response Maintained for 6 Consecutive Months
timeFrame: 104 Weeks
measure: Change From Baseline in Swollen Joint Count at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Tender Joint Count at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Patient's Global Assessment of Disease Activity at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Physicians Global Assessment of Disease Activity at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in the Patient's Pain VAS at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in C-Reactive Protein (CRP) at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Swollen Joint Count at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Tender Joint Count at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Patient's Global Assessment of Disease Activity at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Physicians Global Assessment of Disease Activity at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in the Patient's Pain VAS at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in C-Reactive Protein (CRP) at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants Who Achieve an Improvement of at Least 0.3 Units From Baseline in the HAQ Disability Index at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants Who Achieve an Improvement of at Least 0.3 Units From Baseline in the HAQ Disability Index at Week 104
timeFrame: Baseline, Week 104
measure: Area Under Curve (AUC) of the ACRn to Week 24
timeFrame: 24 Weeks
measure: Area Under Curve (AUC) of the ACRn to Week 52
timeFrame: 52 Weeks
measure: Area Under Curve (AUC) of the ACRn Score at Week 104
timeFrame: 104 Weeks
measure: Change From Baseline in Disease Activity Score (DAS28) at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Disease Activity Score (DAS28) at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Disease Activity Score (DAS28) at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With DAS28 Remission at Week 24
timeFrame: Week 24
measure: Percentage of Participants With DAS28 Remission at Week 52
timeFrame: Week 52
measure: Percentage of Participants With DAS28 Remission at Week 104
timeFrame: Week 104
measure: Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 24
timeFrame: 24 Weeks
measure: Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 52
timeFrame: 52 Weeks
measure: Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 104
timeFrame: 104 Weeks
measure: Change From Baseline in Modified Total Sharp-Genant Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Modified Total Sharp-Genant Score at Week 80
timeFrame: Baseline, Week 80
measure: Change From Baseline in Erosion Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Erosion Score at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Erosion Score at Week 80
timeFrame: Baseline, Week 80
measure: Change From Baseline in Erosion Score at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Joint Space Narrowing Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Joint Space Narrowing Score at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Joint Space Narrowing Score at Week 80
timeFrame: Baseline, Week 80
measure: Change From Baseline in Joint Space Narrowing Score at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With no Progression of Erosion at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With no Progression of Erosion at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants With no Progression of Erosion at Week 104
timeFrame: Baseline, Week 104
measure: Percentage of Participants With no Progression of Joint Space Narrowing at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With no Progression of Joint Space Narrowing at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants With no Progression of Joint Space Narrowing at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in HAQ Disability Index (HAQ-DI) at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in HAQ Disability Index at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Quality Life Short Form-36 (SF-36) Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in SF-36 Score at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in SF-36 Score at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in FACIT-F Score at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in FACIT-F Score at Week 104
timeFrame: Baseline, Week 104
measure: Change From Baseline in Rheumatoid Factor (RF) at Week 24 in Those Patients With Positive RF
timeFrame: Baseline, Week 24
measure: Change From Baseline in Rheumatoid Factor (RF) at Week 52 in Those Patients With Positive RF
timeFrame: Baseline, Week 52
measure: Change From Baseline in Rheumatoid Factor (RF) at Week 104 in Those Patients With Positive RF
timeFrame: Baseline, Week 104
measure: Time to Onset of ACR20 by Treatment Group
timeFrame: 6 months
measure: Time to Onset of ACR50 by Treatment Group
timeFrame: 6 months
measure: Time to Onset of ACR70 by Treatment Group
timeFrame: 6 months
measure: Percentage of Participants Who Withdraw Due to Lack of Sufficient Therapeutic Response
timeFrame: 104 Weeks
measure: Percentage of Participants in Each Treatment Group Who Receive Escape Therapy
timeFrame: 104 Weeks
measure: Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 24
timeFrame: 24 Weeks
measure: Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 52
timeFrame: 52 Weeks
measure: Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 104
timeFrame: 104 Weeks
measure: Percentage of Participants Who Achieved Complete Clinical Response at Week 52
timeFrame: 52 Weeks
measure: Percentage of Participants Who Achieved Complete Clinical Response at Week 104
timeFrame: 104 Weeks
measure: End of Study: Percentage of Participants With ACR Response at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Percentage of Participants With DAS28 Remission at Week 260
timeFrame: Week 260
measure: End of Study: Percentage of Participants With DAS28 Low Disease Activity (LDA) at Week 260
timeFrame: Week 260
measure: End of Study: Percentage of Participants With DAS28 European League Against Rheumatism (EULAR) Good or Moderate Response at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in Swollen Joint Count at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in Tender Joint Count at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in the Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in the Physician's Global Assessment of Disease Activity VAS at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in the Patient's Pain VAS at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Percentage of Participants With Clinical Improvement in the FACIT-Fatigue Score at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Percentage of Participants With Clinical Relevant Improvement in the SF-36 Score at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in Total Sharp-Genant Score at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in Erosion Score at Week 260
timeFrame: Baseline, Week 260
measure: End of Study: Change From Baseline in Joint Space Narrowing Score at Week 260
timeFrame: Baseline, Week 260
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Huntsville
country: United States
state: Alabama
city: Scottsdale
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Anaheim
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Santa Maria
country: United States
state: California
city: Torrance
country: United States
state: California
city: Boulder
country: United States
state: Colorado
city: Colorado Springs
country: United States
state: Colorado
city: Denver
country: United States
state: Colorado
city: Aventura
country: United States
state: Florida
city: Fort Lauderdale
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Boise
country: United States
state: Idaho
city: Coeur D'alene
country: United States
state: Idaho
city: Idaho Falls
country: United States
state: Idaho
city: Meridan
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Rockford
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Lexington
country: United States
state: Kentucky
city: Frederick
country: United States
state: Maryland
city: Hagerstown
country: United States
state: Maryland
city: Wheaton
country: United States
state: Maryland
city: Saint Louis
country: United States
state: Missouri
city: St Louis
country: United States
state: Missouri
city: Billings
country: United States
state: Montana
city: Missoula
country: United States
state: Montana
city: Reno
country: United States
state: Nevada
city: Dover
country: United States
state: New Hampshire
city: Medford
country: United States
state: New Jersey
city: Voorhees
country: United States
state: New Jersey
city: Albany
country: United States
state: New York
city: Brooklyn
country: United States
state: New York
city: Lake Success
country: United States
state: New York
city: New York
country: United States
state: New York
city: Stony Brook
country: United States
state: New York
city: Asheville
country: United States
state: North Carolina
city: Charlotte
country: United States
state: North Carolina
city: Raleigh
country: United States
state: North Carolina
city: Wilmington
country: United States
state: North Carolina
city: Canton
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Tulsa
country: United States
state: Oklahoma
city: Eugene
country: United States
state: Oregon
city: Bethlehem
country: United States
state: Pennsylvania
city: Duncansville
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Wyomissing
country: United States
state: Pennsylvania
city: Columbia
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Olympia
country: United States
state: Washington
city: Seattle
country: United States
state: Washington
city: Glendale
country: United States
state: Wisconsin
city: Adelaide
country: Australia
city: Malvern
country: Australia
city: Melbourne
country: Australia
city: New Lambton
country: Australia
city: Shenton Park
country: Australia
city: St. Leonards
country: Australia
city: Porto Alegre
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Sao Paulo
country: Brazil
city: Sao Paulo
country: Brazil
city: Beijing
country: China
city: Beijing
country: China
city: Nanjing
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Hellerup
country: Denmark
city: Odense
country: Denmark
city: Heinola
country: Finland
city: Helsinki
country: Finland
city: Oulu
country: Finland
city: Vantaa
country: Finland
city: Amiens
country: France
city: Bobigny
country: France
city: Bois Guillaume
country: France
city: Bordeaux
country: France
city: Le Kremlin Bicetre
country: France
city: Lille
country: France
city: Nice
country: France
city: Orleans
country: France
city: Paris
country: France
city: Paris
country: France
city: Strasbourg
country: France
city: Toulouse
country: France
city: Vandoeuvre-les-nancy
country: France
city: Athens
country: Greece
city: Athens
country: Greece
city: Athens
country: Greece
city: Heraklion
country: Greece
city: Brescia
country: Italy
city: Coppito
country: Italy
city: Firenze
country: Italy
city: Genova
country: Italy
city: Milano
country: Italy
city: Milano
country: Italy
city: Napoli
country: Italy
city: Padova
country: Italy
city: Pavia
country: Italy
city: Pisa
country: Italy
city: Reggio Emilia
country: Italy
city: Roma
country: Italy
city: Torino
country: Italy
city: Udine
country: Italy
city: Valeggio Sul Mincio
country: Italy
city: Varese
country: Italy
city: Verona
country: Italy
city: Chihuahua
country: Mexico
city: Mexico City
country: Mexico
city: Mexico City
country: Mexico
city: Mexico City
country: Mexico
city: Mexico City
country: Mexico
city: Monterrey
country: Mexico
city: Obregon
country: Mexico
city: Haugesund
country: Norway
city: Lillehammer
country: Norway
city: Tromsø
country: Norway
city: Bydgoszcz
country: Poland
city: Dzialdowo
country: Poland
city: Elblag
country: Poland
city: Kalisz
country: Poland
city: Krakow
country: Poland
city: Krakow
country: Poland
city: Poznan
country: Poland
city: Szczecin
country: Poland
city: Ustron
country: Poland
city: Warszawa
country: Poland
city: Warszawa
country: Poland
city: Ponce
country: Puerto Rico
city: San Juan
country: Puerto Rico
city: Cape Town
country: South Africa
city: Cape Town
country: South Africa
city: Cape Town
country: South Africa
city: Diepkloof
country: South Africa
city: Barcelona
country: Spain
city: Cádiz
country: Spain
city: Merida
country: Spain
city: Sabadell
country: Spain
city: Santander
country: Spain
city: Sevilla
country: Spain
city: Lausanne
country: Switzerland
city: St. Gallen
country: Switzerland
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Khawaja MN, Bergman MJ, Yourish J, Pei J, Reiss W, Keystone E. Routine Assessment of Patient Index Data 3 and the American College of Rheumatology/European League Against Rheumatism Provisional Remission Definitions as Predictors of Radiographic Outcome in a Rheumatoid Arthritis Clinical Trial With Tocilizumab. Arthritis Care Res (Hoboken). 2017 May;69(5):609-615. doi: 10.1002/acr.23008. Epub 2017 Apr 7.
citation: Kremer JM, Blanco R, Halland AM, Brzosko M, Burgos-Vargas R, Mela CM, Rowell L, Fleischmann RM. Clinical efficacy and safety maintained up to 5 years in patients with rheumatoid arthritis treated with tocilizumab in a randomised trial. Clin Exp Rheumatol. 2016 Jul-Aug;34(4):625-33. Epub 2016 Apr 15.
citation: Bay-Jensen AC, Platt A, Siebuhr AS, Christiansen C, Byrjalsen I, Karsdal MA. Early changes in blood-based joint tissue destruction biomarkers are predictive of response to tocilizumab in the LITHE study. Arthritis Res Ther. 2016 Jan 20;18:13. doi: 10.1186/s13075-015-0913-x.
citation: Keystone EC, Anisfeld A, Ogale S, Devenport JN, Curtis JR. Continued benefit of tocilizumab plus disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis and inadequate clinical responses by week 8 of treatment. J Rheumatol. 2014 Feb;41(2):216-26. doi: 10.3899/jrheum.130489. Epub 2014 Jan 15.
citation: Siebuhr AS, Bay-Jensen AC, Leeming DJ, Plat A, Byrjalsen I, Christiansen C, van de Heijde D, Karsdal MA. Serological identification of fast progressors of structural damage with rheumatoid arthritis. Arthritis Res Ther. 2013 Aug 14;15(4):R86. doi: 10.1186/ar4266.
citation: Fleischmann RM, Halland AM, Brzosko M, Burgos-Vargas R, Mela C, Vernon E, Kremer JM. Tocilizumab inhibits structural joint damage and improves physical function in patients with rheumatoid arthritis and inadequate responses to methotrexate: LITHE study 2-year results. J Rheumatol. 2013 Feb;40(2):113-26. doi: 10.3899/jrheum.120447. Epub 2013 Jan 15.
citation: Wang J, Bansal AT, Martin M, Germer S, Benayed R, Essioux L, Lee JS, Begovich A, Hemmings A, Kenwright A, Taylor KE, Upmanyu R, Cutler P, Harari O, Marchini J, Criswell LA, Platt A. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
citation: Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, Ambs P, Fleischmann R. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011 Mar;63(3):609-21. doi: 10.1002/art.30158.