A Long-term Safety Extension Study of Tocilizumab in Brazilian Participants With Rheumatoid Arthritis (RA) Who Completed the Studies ML21530 and MA21488

Study Overview
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Brief Summary
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This multicenter, open-label, single-arm extension study will evaluate the long-term safety of tocilizumab (RoActemra/Actemra) in participants with RA. Participants who have completed the MA21488 (NCT00810199) core study and the ML21530 (NCT00754572) study and who could benefit from the study drug, according to the opinion of the investigator, will receive 8 milligrams per kilogram (mg/kg) of intravenous (IV) tocilizumab every 4 weeks. The anticipated time on study treatment is 104 weeks.

Official Title
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A Multicenter, Open-Label, Single-Arm Extension Study to Describe the Safety of Tocilizumab Treatment In Brazilian Patients With DMARDs Refractory Rheumatoid Arthritis Which Completed Studies ML21530 and MA21488 and Presenting an Indication of Maintaining the Tocilizumab Treatment

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: DMARDs
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have completed their last visit in the core studies ML21530 and MA21488 and that might benefit from treatment using the study drug according to the investigator's evaluation Absence of an AE or current or recent laboratory finding that would prevent the use of the 8 mg/kg dose of the tocilizumab Receiving outpatient treatment For women who are not postmenopausal and are not surgically sterile: agreement to use at least one adequate method of contraception Exclusion Criteria: Participants who have prematurely discontinued the core studies ML21530 and MA21488 for any reason MA21488 study participants who remained untreated with tocilizumab after it's discontinuation according to the treatment-free remission criteria of MA21488 study Immunization with a live/attenuated vaccine since the last administration of the study drug in the core studies ML21530 and ML21488 Diagnosis after the last visit of the study ML21530 or after the last visit of the study MA21488 of a rheumatic autoimmune disease other than RA, including systemic erythematous lupus (SEL), mixed connective tissue disease (MCTD), scleroderma and polymyositis, or a significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty's syndrome). Secondary Sjogren's Syndrome and/or nodulosis with RA are allowed Diagnosis after the last visit of the core study ML21530 or of the study MA21488 of an inflammatory joint disease other than RA Abnormal laboratory parameters at the baseline History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies Evidences of a concomitant, serious and uncontrolled illness Known active condition or a history of recurrent infections by bacteria, viruses, fungi, mycobacteria or other agents Evidence of an active malignant disease, malignancies diagnosed in the last 10 years or breast cancer diagnosed in the last 20 years Uncontrolled disease status, such as asthma or inflammatory bowel disease in which acute crises are usually treated with oral or parenteral corticosteroids Current hepatic disease, as determined by the investigator Active tuberculosis (TB) requiring treatment in the previous three years. Participants should be screened for latent TB according to local practice guidelines and should not be admitted into the study if latent TB is detected. Participants must not present any evidence of active TB infection at the enrollment. Participants treated for tuberculosis without recurrence in three years are allowed History of alcohol, drugs or chemical abuse since the inclusion in the core studies ML21530 and MA21488

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Participants will receive tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant will be of 800 mg of tocilizumab. Participants may also receive disease-modifying anti-rheumatic drugs (DMARDs) in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance. | Drug: DMARDs<br>* DMARDs may be added to the tocilizumab treatment in any visit, at the discretion of the investigator, according to the local prescription information and participant's tolerance. Study protocol does not specify any particular DMARD.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered at 8 mg/kg IV dose every 4 weeks for 104 weeks<br>* Other names: RoActemra; Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (NSAEs) | An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; significant medical event, according to the investigator discretion (e.g., may represent a risk to the participant or may require medical/surgical intervention to prevent one of the outcomes mentioned above). | From Baseline up to approximately 2 years | 
| Number of Participants With AEs Leading to Dose Modification or Study Discontinuation |  | From Baseline up to approximately 2 years | 
| Number of Participants With AEs of Special Interest | Adverse events of special interest included following events: Infections (including opportunistic infections); myocardial infarction / acute coronary syndrome; gastrointestinal (GI) perforations and related events; malignancies; anaphylaxis/hypersensitivity reactions; demyelinating disorders; stroke; hemorrhagic events; and hepatic events. Overall number of participants who experienced any of these AEs of special interest was reported. | From Baseline up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) | DAS28 score is a measure of participant's disease activity calculated using tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), participant's global assessment of disease activity (general health [GH]) using visual analog scale (VAS), 0 millimeter (mm)=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (erythrocyte sedimentation rate [ESR] in millimeters per hour [mm/hr]) for a total possible score of 0 to 10. The score is calculated using the following formula: DAS28 = [0.56 multiplied by (*) square root (√) of TJC28] plus (+) [0.28*√SJC28]+[0.70*the natural logarithm (ln) ESR]+[0.014*GH]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and follow-up (FU) Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Tender Joint Count (TJC) | An assessment of 28 joints was conducted for tenderness. Joints were assessed and classified as tender/not tender by pressure and joint manipulation after a physical examination. Artificial joints, arthrodesis or fused joints were not taken into consideration for tenderness. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Swollen Joint Count (SJC) | An assessment of 28 joints was conducted for swelling. Joints were assessed and classified as swollen/not swollen by pressure and joint manipulation after a physical examination. Artificial joints, arthrodesis or fused joints were not taken into consideration for swelling. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Global Evaluation of Disease Activity by the Participant Using VAS Score | Participant's global assessment of disease activity was measured on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as inactive disease (free of symptoms and without symptoms of arthritis) and 100 mm (right end of the line) as disease maximum activity (maximum activity of arthritis). The participant marked the line according to their assessment and the distance from the left edge was measured. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Global Evaluation of Disease Activity by the Physician Using VAS Score | Physician global assessment of disease activity was measured on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as inactive disease (free of symptoms and without symptoms of arthritis) and 100 mm (right end of the line) as disease maximum activity (maximum activity of arthritis). The physician marked the line according to their assessment and the distance from the left edge was measured. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Participant's Pain Assessment Using VAS Score | Participant's pain assessment was made on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as no pain and 100 mm (right end of the line) as unbearable pain. The participant marked the line according to their assessment and the distance from the left edge was measured. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Health Assessment Questionnaire - Disability Index (HAQ-DI) Score | The Stanford HAQ-DI is a participant-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/personal care, ability to stand-up, eating, walking, hygiene, reaching, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where 0 represents 'no disability' and 3 represents 'very severe, high-dependency disability'. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| Health Assessment Questionnaire (HAQ) Pain VAS Score | The HAQ pain VAS is a measure of pain on a continuous 100 mm scale. Participants were asked to indicate how much pain they had in the past week as a result of their illness on a horizontal line from 0 (no pain) to 100 mm (severe pain). | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| C-Reactive Protein (CRP) Level | CRP is an acute phase reactant and is a measure of inflammation. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) | 
| ESR Level | ESR is an acute phase reactant and is a measure of inflammation. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116) |