A Study of RoActemra/Actemra (Tocilizumab) in Combination With Methotrexate Versus RoActemra/Actemra Monotherapy in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

A Multi-center Study of the Safety and Effect on Disease Activity of Tocilizumab (TCZ) in Combination With MTX Versus Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis, With Inadequate Response to MTX (Defined as DAS 28 > 3,2)

This randomized, double-blind, parallel-group study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in combination with methotrexate versus RoActemra/Actemra monotherapy in patients with rheumatoid arthritis and an inadequate response to methotrexate. All patients will receive RoActemra/Actemra 8 mg/kg intravenously (iv) every 4 weeks plus oral methotrexate for 16 weeks. Patients achieving low disease activity at Week 16 will be randomized to receive a further 12 weeks of RoActemra/Actemra treatment plus either methotrexate or placebo. Anticipated time on study treatment is 28 weeks.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: methotrexate; Drug: methotrexate; Drug: tocilizumab [RoActemra/Actemra]; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 261
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Albacete, Spain, 02006
  • Badajoz, Spain, 06080
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08003
  • Barcelona, Spain, 08035
  • Barcelona, Spain, 08907
  • Barcelona, Spain, 08025
  • Caceres, Spain, 10310
  • Cordoba, Spain, 14004
  • Granada, Spain, 18014
  • Granada, Spain, 18003
  • Guadalajara, Spain, 19002
  • Leon, Spain, 24071
  • Lugo, Spain, 27004
  • Madrid, Spain, 28040
  • Madrid, Spain, 28046
  • Madrid, Spain, 28034
  • Madrid, Spain, 28905
  • Madrid, Spain, 28041
  • Madrid, Spain, 28007
  • Madrid, Spain, 28031
  • Malaga, Spain, 29009
  • Salamanca, Spain, 37007
  • Sevilla, Spain, 41013
  • Sevilla, Spain, 41009
  • Tenerife, Spain, 38010
  • Toledo, Spain, 45004
  • Valencia, Spain, 46017
  • Valencia, Spain, 46010
  • Alicante
    • Orihuela, Alicante, Spain, 03314
    • Torrevieja, Alicante, Spain, 03186
    • Villajoyosa, Alicante, Spain, 03570
  • Badajoz
    • Merida, Badajoz, Spain, 06800
  • Barcelona
    • Badalona, Barcelona, Spain, 08915
    • Granollers, Barcelona, Spain, 08402
    • Terrassa, Barcelona, Spain, 08221
  • Cadiz
    • Cádiz, Cadiz, Spain, 11009
  • Cantabria
    • Torrelavega, Cantabria, Spain, 39300
  • Castellon
    • Villarreal, Castellon, Spain, 12540
  • Islas Baleares
    • Menorca, Islas Baleares, Spain, 07701
  • La Coruña
    • A Coruna, La Coruña, Spain, 15006
    • Santiago de Compostela, La Coruña, Spain, 15706
  • Las Palmas
    • Las Palmas De Gran Canaria, Las Palmas, Spain, 35020
  • Madrid
    • Alcala de Henares, Madrid, Spain, 28805
    • Fuenlabrada, Madrid, Spain, 28942
    • Valdemoro, Madrid, Spain, 28342
  • Murcia
    • Cartagena, Murcia, Spain, 30203
    • El Palmar, Murcia, Spain, 30120
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36214
  • Valencia
    • Manises, Valencia, Spain, 46940
    • Valenica, Valencia, Spain, 46009
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
    • Bilbao, Vizcaya, Spain, 48013
    • Galdakao, Vizcaya, Spain, 48960

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, >/= 18 years of age
• Active moderate to severe rheumatoid arthritis (DAS28 >/= 3.2) at baseline
• Currently receiving methotrexate for at least 12 weeks, at a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1)
• Body weight < 150 kg
• Oral corticoids must have been at stable dose for at least 25 out of 28 days prior to baseline; maximum dose 10 mg/day

Exclusion Criteria:

• Pregnant or nursing women
• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months after baseline
• Rheumatic autoimmune disease other than RA
• Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis
• Prior history of or current inflammatory joint disease other than RA
• Treatment with a biologic agent at any time prior to baseline
• Treatment with traditional DMARDs other than methotrexate within 1 month (for leflunomide 3 months) prior to baseline
• Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline
• Previous treatment with RoActemra/Actemra
• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
• Known active current or history of recurrent infection
• History of or currently active primary or secondary immunodeficiency
• Active tuberculosis requiring treatment within the previous 3 years
• Positive for HIV infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: A	Drug: methotrexate; orally, Week 1 - 16; Drug: methotrexate; orally, Week 17-28; Drug: tocilizumab [RoActemra/Actemra]; 8 mg/kg iv every 4 weeks, 28 weeks
ACTIVE_COMPARATOR: B	Drug: methotrexate; orally, Week 1 - 16; Drug: methotrexate; orally, Week 17-28; Drug: tocilizumab [RoActemra/Actemra]; 8 mg/kg iv every 4 weeks, 28 weeks; Drug: placebo; methotrexate placebo orally, Week 17-28

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28	The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (erythrocyte sedimentation rate [ESR] in millimeters per hour [mm/hr]), and general health status (participant global assessment of disease activity using visual analog scale [VAS], range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.	Baseline, Week 16, and Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28	The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 <2.6 equals (=) remission.	Week 28
Percentage of Participants With Clinical Disease Activity Index (CDAI) <2.8 at Week 28	CDAI is the sum of tender and swollen joint count based on 28 joints and the participant and physician global disease assessment (VAS 0-10 centimeters [cm]). CDAI total score 0-76; higher scores = greater affect due to disease activity. CDAI <2.8 = clinical remission.	Week 28
Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28	SDAI is calculated by a simple numerical sum of tender and swollen joint count (based on a 28-joint assessment), participant and physician global assessment of disease activity (VAS 0-10 cm), and level of C-reactive protein in milligram per deciliter (mg/dL). SDAI total score 0-86; higher scores = greater affect due to disease activity. SDAI <3.3 = clinical remission.	28 weeks
Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28	HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.	Week 16 and Week 28
Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health	Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated decline in health and higher scores indicated improvement in health.	Week 16 and Week 28
Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health	Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated a worsening of quality of life.	Week 16 and Week 28
Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant	Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm.	Week 16 and Week 28
Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator	Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm.	Week 16 and Week 28

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (ACTUAL): May 1, 2014
• Study Completion (ACTUAL): May 1, 2014

Study Registration Dates

• First Submitted: July 20, 2011
• First Submitted That Met QC Criteria: July 20, 2011
• First Posted (ESTIMATE): July 22, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): July 13, 2015
• Last Update Submitted That Met QC Criteria: June 18, 2015
• Last Verified: May 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: ML27828