A Study of RoActemra/Actemra (Tocilizumab) Versus Adalimumab in Combination With Methotrexate (MTX) in Patients With Moderate to Severe Active Rheumatoid Arthritis And an Inadequate Response to Treatment With Only One Tumor Necrosis Factor (TNF)-Inhibitor

Study Overview
=================
Brief Summary
-----------------
This randomized, parallel-group study will assess the efficacy and safety of RoActemra/Actemra (tocilizumab) versus adalimumab, both in combination with methotrexate (MTX) in patients with moderate to severe active rheumatoid arthritis. Patients, already treated with MTX at stable doses, will be randomized to receive either RoActemra/Actemra 8 mg/kg intravenously (IV) every 4 weeks or adalimumab 40 mg subcutaneous (SC) every 2 weeks. All patients will receive methotrexate (10-25 mg weekly) and folate (at least 5 mg weekly). The anticipated time on study treatment is 24 weeks.

Official Title
-----------------
A Randomized, Open-label, Parallel-group Study of the Reduction of Signs and Symptoms During Treatment With Tocilizumab Versus Adalimumab, Both in Combination With MTX, in Patients With Moderate to Severe Active Rheumatoid Arthritis and an Inadequate Response to Treatment With Only One TNF Inhibitor

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: tocilizumab [RoActemra/Actemra]
* Drug: adalimumab
* Drug: placebo to tocilizumab
* Drug: placebo to adalimumab
* Drug: methotrexate
* Drug: folate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients, >/= 18 years of age Rheumatoid arthritis of >/= 6 months duration (according to American College of Rheumatology (ACR) criteria)(according to ACR criteria) Inadequate response due to inefficacy of treatment (for at least 3 months) with only one approved Tumor Necrosis Factor (TNF)-agent other than adalimumab Depending on the TNF-inhibitor, last dose of TNF-inhibitor should have been 1 to 8 weeks before randomization to the study On methotrexate treatment for >/=12 weeks immediately prior to baseline, with stable dose (10-25 mg/week) for the last 8 weeks Disease Activity Score (DAS28) >3.2 at baseline Oral corticosteroids (</=10 mg/day prednisone or equivalent) and non-steroidal anti-inflammatory drugs (NSAIDs) are permitted if the dose has been stable for >/=6 weeks prior to baseline. Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to screening or planned surgery within 6 months following randomization Rheumatic autoimmune disease other than rheumatoid arthritis Prior history of or current inflammatory joint disease other than rheumatoid arthritis Functional class IV (ACR criteria) History of severe allergic reaction to human, humanized or murine monoclonal antibodies Known active current or history of recurrent infection (including tuberculosis) Primary or secondary immunodeficiency (history of or currently active) Body weight >150 kg Previous treatment with any cell-depleting therapies Previous treatment with tocilizumab Intra-articular or parenteral corticosteroids within 6 weeks prior to baseline.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab + Methotrexate<br>Tocilizumab 8 mg/kg intravenous (IV) every 4 weeks + Placebo to adalimumab subcutaneous (SC) every 2 weeks for 24 weeks. All participants received methotrexate 10-25 mg and folate at least 5 mg/kg weekly. | Drug: tocilizumab [RoActemra/Actemra]<br>* Tocilizumab 8 mg/kg IV every 4 weeks for 24 weeks.<br>* Other names: RoActemra/Actemra;Drug: placebo to adalimumab<br>* Placebo to adalimumab SC every 2 weeks for 24 weeks.<br>Drug: methotrexate<br>* Methotrexate 10-25 mg weekly.<br>Drug: folate<br>* Folate at least 5 mg weekly.<br>|
| Active Comparator: Adalimumab + Methotrexate<br>Adalimumab 40 mg SC every 2 weeks + Placebo to tocilizumab IV every 4 weeks for 24 weeks. All participants received methotrexate 10-25 mg and folate at least 5 mg/kg weekly. | Drug: adalimumab<br>* Adalimumab 40 mg SC every 2 weeks.<br>Drug: placebo to tocilizumab<br>* Placebo to tocilizumab IV every 4 weeks for 24 weeks.<br>Drug: methotrexate<br>* Methotrexate 10-25 mg weekly.<br>Drug: folate<br>* Folate at least 5 mg weekly.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease Activity Score 28 Joints (DAS28) Remission at Week 24 | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 2 to 10. DAS28 Remission is defined as a DAS28 score <2.6. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With American College of Rheumatology (ACR20) Response at Week 24 | ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 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 Erythrocyte Sedimentation Rate. | Baseline, Week 24 | 
| Percentage of Participants With ACR50 Response at Week 24 | ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 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 Erythrocyte Sedimentation Rate. | Baseline, Week 24 | 
| Percentage of Participants With ACR70 Response at Week 24 | ACR70 response is defined as a ≥ 70% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 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 Erythrocyte Sedimentation Rate. | Baseline, Week 24 | 
| Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) DAS28 Responses at Week 24 | The DAS28 score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28 total score ranges from 0 (best) to 10 (worst). A negative change from Baseline indicated improvement. European League Against Rheumatism (EULAR) Good response: DAS28 ≤ 3.2 or a change from Baseline < -1.2. EULAR Moderate response: DAS28 >3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2. | Baseline, Week 24 | 
| Percentage of Participants With DAS28 Low Disease Activity (LDAS) at Week 24 | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 2 to 10. LDAS is defined as DAS28 ≤3.2. | Week 24 | 
| Change From Baseline in DAS28 Score at Week 24 | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 2 to 10. A higher value indicated higher disease activity. A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in Swollen Joint Count (SJC) at Week 24 | 66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in Tender Joint Count (TJC) at Week 24 | 68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in Patient Assessment of Pain Visual Analog Scale (VAS) at Week 24 | The patient assessed their pain using a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as no pain and the right-hand extreme equals 100 mm as unbearable pain. A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in the Patient Global Assessment of Disease Activity VAS at Week 24 | The patient's global assessment of disease activity is assessed on a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as maximum disease activity (maximum arthritis disease activity). A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in the Physician Global Assessment of Disease Activity VAS at Week 24 | The physician global assessment of disease activity was assessed using a 0 to 100 mm horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as maximum disease activity (maximum arthritis disease activity). A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) at Week 24 | Blood was collected for C-Reactive Protein (CRP) (a test for analysis of inflammatory and infectious disorders) and was analyzed at a central laboratory. The concentration of CRP was measured in milligram/liter (mg/L). A reduction in the level is considered an improvement | Baseline, Week 24 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 24 | Blood was collected for Erythrocyte Sedimentation Rate (ESR) (a test that assesses tissue inflammation) and was analyzed at a local laboratory. ESR was measured in millimeter/hour (mm/hr). A reduction in the level is considered an improvement. | Baseline, Week 24 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 | The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from Baseline indicated improvement. | Baseline, Week 24 | 
| Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) Score at Week 24 | FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status. A positive change from Baseline indicates improvement. | Baseline, Week 24 | 
| Change From Baseline in Quality of Life Short Form (SF-36) Score at Week 24 | The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. | Baseline, Week 24 | 
| Change From Baseline in Routine Assessment of Patient Index Data 3 (RAPID3) Score at Week 24 | RAPID3 is a patient self reported assessment that combines the HAQ-DI [20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions answered on a 4-point scale where 0=without any difficulty to 3=unable to do} converted to a score of 0-10, the Patients Assessment of Pain [Over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain] converted to a score of 0-10 and the Patient's Global Assessment of Disease Activity [over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity] converted to a score of 0-10. The 3 individual scales are summed for a raw score of 0-30 which is divided by 3 to achieve a total possible adjusted score of 0-10. A negative change from Baseline indicates improvement. | Baseline, Week 24 | 
| Change From Baseline in Hemoglobin at Week 24 | Blood was collected at Baseline and Week 24. The samples were sent to a central laboratory for Hemoglobin analysis reported in gram/deciliter (g/dL). A positive number change from Baseline (a higher hemoglobin level compared to Baseline) indicated improvement | Baseline, Week 24 | 
| Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Discontinuation Due to AEs and Deaths | An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. | 32 weeks |