A Study of RoActemra/Actemra (Tocilizumab) Given Subcutaneously in Combination With Traditional DMARDs in Patients With Moderate to Severe Active Rheumatoid Arthritis

A Randomized, Double-blind, Parallel Group Study of Safety and the Effect on Clinical Outcome of Tocilizumab Subcutaneous (sc) Versus Placebo sc in Combination With Traditional Disease Modifying Anti-rheumatic Drugs (DMARDs) in Patients With Moderate to Severe Active Rheumatoid Arthritis

This randomized, parallel-group, placebo-controlled, multicenter study will evaluate the reduction in disease activity and the safety of tocilizumab (RoActemra/Actemra) in combination with traditional disease-modifying anti-rheumatic drugs (DMARDs) in patients with active, moderate to severe rheumatoid arthritis. In the double-blind part of the study, patients will be randomized to receive either 162 mg tocilizumab or placebo subcutaneously every 2 weeks for 24 weeks using a pre-filled syringe. In the open-label part of the study, patients will be randomized to receive 162 mg tocilizumab subcutaneously every 2 weeks from Week 24 to Week 96 using a pre-filled syringe or an auto-injector.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Tocilizumab 162 mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 656
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1015ABO
  • Córdoba, Argentina, 5000
  • San Miguel de Tucuman, Argentina, 4000
• Australia
  • Cairns, Australia, 4870
  • Kogarah, Australia, 2217
• Brazil
  • Curitiba, Brazil, 80060-240
  • Goiania, Brazil, 74043-011
  • Juiz de Fora, Brazil, 36010-570
  • Porto Alegre, Brazil, 90610-000
  • Porto Alegre, Brazil, 91350-200
  • Rio de Janeiro, Brazil, 22271-100
  • Salvador, Brazil, 40050-410
  • Sao Paulo, Brazil, 04266-010
  • Sao Paulo, Brazil, 05437-010
  • Sao Paulo, Brazil, 5403900
  • São Paulo, Brazil, 04026-000
  • São Paulo, Brazil, 1244030
  • Vitoria, Brazil, 29055-450
• Bulgaria
  • Plovdiv, Bulgaria, 4002
  • Plovdiv, Bulgaria, 4003
  • Sofia, Bulgaria, 1612
  • Sofia, Bulgaria, 2233
  • Varna, Bulgaria, 9010
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3N 0K6
    • Winnipeg, Manitoba, Canada, R3A 1M3
  • Ontario
    • London, Ontario, Canada, N6A 4V2
    • Ottawa, Ontario, Canada, K1H 1A2
  • Quebec
    • Pointe-claire, Quebec, Canada, H9R 3J1
• Colombia
  • Bogota, Colombia
  • Chia-cundinamarca, Colombia
  • Medellin, Colombia
• Greece
  • Athens, Greece, 11527
  • Athens, Greece, 15121
  • Thessaloniki, Greece, 54636
• Guatemala
  • Guatemala City, Guatemala, 01015
  • Guatemala City, Guatemala, 01010
  • Guatemala City, Guatemala, 01013
• Hungary
  • Budapest, Hungary, 1036
  • Debrecen, Hungary, 4004
• Israel
  • Ashkelon, Israel, 78306
  • Beer Sheva, Israel, 84101
  • Haifa, Israel, 31048
  • Haifa, Israel, 31096
  • Ramat Gan, Israel, 52621
  • Rishon Lezion, Israel
  • Tel Aviv, Israel, 64239
• Malaysia
  • Batu Caves, Malaysia, 68100
  • Kota Kinabalu, Malaysia, 88586
  • Kuala Lumpur, Malaysia, 50603
• Mexico
  • Chihuahua, Mexico, 31000
  • Culiacan, Mexico, 80000
  • Guadalajara, Mexico, 44158
  • Leon, Mexico, 37320
  • Merida, Mexico, 97000
  • Mexicali, Mexico, 21100
  • Mexico, Mexico, 44620
  • Morelia, Mexico, 58070
  • Obregon, Mexico, 85000
  • Queretaro, Mexico, 76000
  • Queretaro, Mexico, 76178
• New Zealand
  • Otahuhu, New Zealand, 1006
• Panama
  • Panama City, Panama, 32400
• Philippines
  • Cebu, Philippines, 6000
  • Davao, Philippines, 8006
  • Manila, Philippines, 1780
• Poland
  • Bytom, Poland, 41902
  • Dzialdowo, Poland, 13-200
  • Elblag, Poland, 82-300
  • Koscian, Poland, 64-000
  • Krakow, Poland, 31-121
  • Torun, Poland, 87-100
  • Warszawa, Poland, 02-653
• Russian Federation
  • Kemerovo, Russian Federation, 650099
  • Moscow, Russian Federation, 115522
  • Moscow, Russian Federation, 117049
  • Moscow, Russian Federation, 129327
  • Novosibirsk, Russian Federation, 630099
  • Petrozavodsk, Russian Federation, 185019
  • Ryazan, Russian Federation, 390026
  • Saint-petersburg, Russian Federation, 197341
  • St Petersburg, Russian Federation, 197022
  • St Petersburg, Russian Federation, 190068
  • UFA, Russian Federation, 450005
  • Voronezh, Russian Federation, 394066
• South Africa
  • Durban, South Africa, 4013
  • Pinelands, South Africa, 7405
  • Pretoria, South Africa, 0002
• Spain
  • La Coruna, Spain, 15006
  • Oviedo, Spain, 33006
  • Sevilla, Spain, 41009
• Switzerland
  • Fribourg, Switzerland, 1708
  • Genève, Switzerland, 1211
  • Lausanne, Switzerland, 1011
  • Zürich, Switzerland, 8063
• Thailand
  • Bangkok, Thailand, 10400
  • Bangkok, Thailand, 10700
• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
    • Scottsdale, Arizona, United States, 85258
    • Tucson, Arizona, United States, 85724
    • Tucson, Arizona, United States, 85723
  • California
    • Fullerton, California, United States, 92835
    • San Diego, California, United States, 92108
    • San Leandro, California, United States, 94578
    • West Hills, California, United States, 91307
  • Connecticut
    • Trumbull, Connecticut, United States, 06611
  • Florida
    • Boca Raton, Florida, United States, 33486
    • Jupiter, Florida, United States, 33458
    • Ormond Beach, Florida, United States, 32174
    • Sarasota, Florida, United States, 34292
  • Georgia
    • Gainesville, Georgia, United States, 30501
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
    • Meridan, Idaho, United States, 83642
  • Illinois
    • Springfield, Illinois, United States, 62704
    • Vernon Hills, Illinois, United States, 60061
  • Maryland
    • Crofton, Maryland, United States, 21114
    • Hagerstown, Maryland, United States, 21740
    • Wheaton, Maryland, United States, 20902
  • Mississippi
    • Flowood, Mississippi, United States, 39232
    • Jackson, Mississippi, United States, 39202
  • Missouri
    • Saint Louis, Missouri, United States, 63128
    • St Louis, Missouri, United States, 63141
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
  • New York
    • Brooklyn, New York, United States, 11201
  • North Carolina
    • Belmont, North Carolina, United States, 28012
    • Charlotte, North Carolina, United States, 28207
    • Charlotte, North Carolina, United States, 28204
    • Charlotte, North Carolina, United States, 28211
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
    • Bethlehem, Pennsylvania, United States, 18015
    • Duncansville, Pennsylvania, United States, 16635
    • Wexford, Pennsylvania, United States, 15090
    • Wyomissing, Pennsylvania, United States, 19610
  • Tennessee
    • Memphis, Tennessee, United States, 38104
  • Texas
    • Dallas, Texas, United States, 75246
    • Fort Worth, Texas, United States, 76107
    • Houston, Texas, United States, 77034
    • Houston, Texas, United States, 77459
    • San Antonio, Texas, United States, 78232
  • Washington
    • Tacoma, Washington, United States, 98405

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

Inclusion Criteria:

• Adult patients, ≥ years of age.
• Moderate to severe rheumatoid arthritis of ≥ 6 months duration.
• Receiving treatment on an outpatient basis.
• Swollen joint count (SJC) ≥ 6 (66 joint count) and tender joint count (TJC)≥ 8 (68 joint count) at screening and study start.
• On a stable dose of disease-modifying anti-rheumatic drugs for at least 8 weeks prior to study start.

Exclusion Criteria:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
• Rheumatic autoimmune disease other than rheumatoid arthritis, Secondary Sjögren's Syndrome with rheumatoid arthritis is allowed.
• Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis.
• Diagnosis of juvenile idiopathic arthritis or juvenile rheumatoid arthritis and/or rheumatoid arthritis before the age of 16 years.
• Prior history of or current inflammatory joint disease other than rheumatoid arthritis.
• History of malignancy, active or recurrent infections, positive to hepatitis B surface antigen or hepatitis C antibody, active tuberculosis, serious allergy to biologics, or a history of diverticular disease or other symptomatic GI conditions that might predispose to perforations.

Other inclusion and exclusion criteria applied to the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tocilizumab 162 mg sc; Patients will receive tocilizumab 162 mg subcutaneously (sc) every 2 weeks for 24 weeks.	Drug: Tocilizumab 162 mg; Tocilizumab will be supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers will be trained to administer the injection.; Other Names: RoActemra; Actemra
Placebo Comparator: Placebo sc; Patients will receive placebo subcutaneously (sc) every 2 weeks for 24 weeks.	Drug: Placebo; Placebo will be supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers will be trained to administer the injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With an American College of Rheumatology 20 (ACR20) Response at Week 24	A patient had an ACR20 response if there was at least a 20% improvement, ie, reduction from baseline, in tender and swollen joint counts (28 assessed joints) and in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, left end=no disease activity [symptom-free and no arthritis symptoms], right end=maximum disease activity; patient assessment of pain in previous 24 hours on a VAS (left end=no pain and right end=unbearable pain); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and acute-phase reactant (either C-reactive protein or erythrocyte sedimentation rate).	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With ACR50 and ACR70 Responses at Week 24	A patient had an ACR50 response if there was at least a 50% improvement in the ACR scores. A patient had an ACR70 response if there was at least a 70% improvement in the ACR scores.	Baseline to Week 24
Time to Onset of ACR20, ACR50, and ACR70 Responses	Time to first ACR response was calculated as the number of days between the date of the first ACR response minus the date of the first dose of study drug. Median days are reported.	Baseline to Week 24
Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 24	Joints (28 joints) will be assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation on physical examination.	Baseline to Week 24
Change From Baseline in C-reactive Protein at Week 24		Baseline to Week 24
Change From Baseline in Erythrocyte Sedimentation Rate at Week 24		Baseline to Week 24
Change From Baseline in the Patient's and the Physician's Global Assessment of Disease Activity Visual Analog (VAS) Score	Patients and physicians assessed the patient's disease activity in the previous 24 hours on a 100 mm visual analog scale, where the extreme left end of the line represented "no disease activity" (symptom-free and no arthritis symptoms) and the extreme right end represented "maximum disease activity". Scores ranged from 0 to 100 with a higher score indicating more disease activity. A negative change score indicated less disease activity.	Baseline to Week 24
Change From Baseline in the Patient's Pain Visual Analog Score	Patients assessed their pain in the previous 24 hours on a visual analog scale, where the extreme left end of the line represented "no pain" and the extreme right end represented "unbearable pain". Scores ranged from 0 to 100 with a higher score indicating more pain. A negative change score indicated less pain.	Baseline to Week 24
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24	The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Patients completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.	Baseline to Week 24
Percentage of Patients With an Improvement of ≥ 0.3 Units From Baseline in the HAQ-DI Score at Week 24	The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Patients completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.	Baseline to Week 24
Change From Baseline in Disease Activity Score 28 (DAS28) at Week 24	The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement.	Baseline to Week 24
Percentage of Patients With a DAS28 Score ≤ 3.2 (DAS28 Low Disease Activity) at Week 24	The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement.	Baseline to Week 24
Percentage of Patients With a DAS28 Score < 2.6 (DAS28 Remission) at Week 24	The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement.	Week 24
Percentage of Patients With Good, Moderate, or no European League Against Rheumatism (EULAR) Responses at Week 24	Change of the Disease Activity Score 28 score from baseline was used to determine EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2.	Baseline to Week 24
Change From Baseline in the Van Der Heijde Modified Sharp Radiographic Score at Week 24	The degree of joint damage was assessed using the van der Heijde modified total Sharp score (mTSS). The methodology quantifies the extent of bone erosions for 44 joints and joint space narrowing (JSN) for 42 joints, with higher scores representing greater damage. The independent read of X-ray images was performed by 2 primary readers. In case of discrepancy between the 2 primary readers, an adjudicator was involved. The mTSS can range from 0 to 448 with a higher score indicating more joint damage. A negative change score indicates improvement.	Baseline to Week 24
Change From Baseline in the Physical and Mental Component Scores of the Short Form 36 (SF-36) Health Survey at Week 24	The SF-36 Health Survey uses patient-reported symptoms on 8 subscales to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100 with a higher score indicating better HRQoL. A positive change score indicates an improvement in HRQoL.	Baseline to Week 24
Change From Baseline in Hemoglobin at Week 24		Baseline to Week 24

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Kivitz A, Olech E, Borofsky M, Zazueta BM, Navarro-Sarabia F, Radominski SC, Merrill JT, Rowell L, Nasmyth-Miller C, Bao M, Wright S, Pope JE. Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014 Nov;66(11):1653-61. doi: 10.1002/acr.22384.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: November 1, 2010
• First Submitted That Met QC Criteria: November 1, 2010
• First Posted (Estimate): November 2, 2010

Study Record Updates

• Last Update Posted (Estimate): July 29, 2015
• Last Update Submitted That Met QC Criteria: July 7, 2015
• Last Verified: July 1, 2015

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
• Other Study ID Numbers: NA25220; 2010-019912-18 (EudraCT Number)