A Study of RoActemra/Actemra (Tocilizumab) in Combination With Methotrexate in Patients With Severe Active Rheumatoid Arthritis, Comparing Tapering Versus Maintaining the Methotrexate Dosage

Study Overview
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Brief Summary
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This randomized, placebo-controlled, double-blind study will compare the safety and efficacy of tapering methotrexate (MTX) versus maintaining MTX dosage in patients with severe active rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) initiated on treatment with tocilizumab. Participants will receive tocilizumab 8 mg/kg intravenously every 4 weeks and MTX orally weekly throughout the study. At Week 24, participants achieving a good/moderate EULAR response will be randomized receiving the MTX Tapering arm or MTX Maintenance arm. Up to Week 56 participants will receive either tapering or stable dose MTX in combination with tocilizumab. From Week 56 to Week 72 participants will receive tocilizumab monotherapy.

Official Title
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Randomized, Phase IV, Placebo-controlled, Comparative Study to Evaluate the Efficacy and Safety of Tapering Methotrexate (MTX) Dosage Versus Maintaining the Dosage in Patients With Severe Active Rheumatoid Arthritis (RA) Who Have Demonstrated an Inadequate Response (IR) to Prior Disease-modifying Anti-rheumatic Drugs (DMARDs) Treatment and Have Initiated RoActemra (RoActemra, TCZ) in Combination With MTX

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Methotrexate (stable dose)
* Drug: Tocilizumab
* Drug: Methotrexate (tapering dose)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Active severe rheumatoid arthritis (DAS28 > 5.1) according to European League of Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria Inadequate response to a trial of 2 DMARDs, including methotrexate, a trial being defined as 6 months with 2 months at standard dose; no previous treatment with a biologic agent such as a tumor necrosis factor (TNF) inhibitor Oral corticosteroids must have been at a stable dose of </= 10 mg/day prednisolone or equivalent for at least 25 out of 28 days prior to start of treatment (Day 1) 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 Functional class IV as defined by the ACR Classification of Functional Status in RA Prior history of or current inflammatory joint disease other than RA Previous treatment with tocilizumab Previous treatment with any biologic drug (e.g. TNF inhibitor) that is used in the treatment of RA Intraarticular or parenteral corticosteroids within 6 weeks prior to enrollment Inadequate liver, bone marrow or hepatic function Positive for hepatitis B, hepatitis C or HIV infection Pregnant or breastfeeding women Females of child-bearing potential who are not using reliable means of contraception History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies Active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections History of, or currently active, primary or secondary immunodeficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate (MTX) Tapering Dosage<br>At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks. At Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response will be randomized to the MTX Tapering group or MTX Maintenance group. In this arm participants will receive a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. Participants will also continue to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants will receive tocilizumab monotherapy. | Drug: Tocilizumab<br>* 8 mg/kg intravenously every 4 weeks for 72 weeks<br>* Other names: RoActemra/Actemra;Drug: Methotrexate (tapering dose)<br>* Tapering doses of methotrexate (MTX) were administered weekly from Week 24 to Week 56. Tapering doses depended on dose administered to the subject during the open label period. First tapering occurred at randomization (Week 24), second tapering at Week 32, third tapering at Week 40 and final tapering at Week 48.<br>|
| Active Comparator: Methotrexate (MTX) Maintenance Dosage<br>At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks. At Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response will be randomized to the MTX Tapering group or MTX Maintenance group. In this arm participants will continue to be administered a stable dose of MTX in a double-blind fashion between Week 24 and Week 56. Participants will also continue to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants will receive tocilizumab monotherapy. | Drug: Methotrexate (stable dose)<br>* Methotrexate (MTX) was administered weekly according to the subject's pre-study MTX dose<br>Drug: Tocilizumab<br>* 8 mg/kg intravenously every 4 weeks for 72 weeks<br>* Other names: RoActemra/Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60 | Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (<=) 3.2 and reduction of greater than (>) 1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score <=5.1 with reduction of >0.6 to <=1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to <=1.2 points, or any score with reduction <=0.6 points, were assessed as non-responders with response recorded as 'none.' | From randomization to Week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 | The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Randomization (Week 24), Week 60 | 
| Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72 | The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. | Randomization (Week 24), Week 72 | 
| Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28. | Week 60, 72 | 
| Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 | The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve score <=3.2 at weeks 60 and 72 were reported. | Week 60, 72 | 
| Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) | The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve DAS28 remission score <2.6 at weeks 60 and 72 were reported. | Week 60, 72 | 
| Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 | The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve cDAS28 >=1.2 score at weeks 60 and 72 were reported. | Week 60, 72 | 
| Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 | Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. | Randomization (Week 24), Week 60, 72 | 
| Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 | Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. | Randomization (Week 24), Week 60, 72 | 
| Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 | The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score. | Randomization (Week 24), Week 60, 72 | 
| Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 | The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score. | Randomization (Week 24), Week 60, 72 | 
| Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 | 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. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score. | Randomization (Week 24), Week 60, 72 | 
| Percentage of Participants With Anemia |  | Week 0 up to Week 72 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment. | Week 0 up to Week 72 | 
| Percentage of Participants Able to Discontinue Methotrexate |  | Week 0 up to Week 60 | 
| Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) | The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. | Randomization (Week 24), Week 60, 72 | 
| Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72. | Randomization (Week 24), Week 60, Week 72 | 
| Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact. | Randomization (Week 24), Week 60, 72 |