A Long Term Extension Study of WA19926 (NCT01007435) of Tocilizumab (RoActemra/Actemra) in Participants With Early, Moderate to Severe Rheumatoid Arthritis (RA)

Study Overview
=================
Brief Summary
-----------------
This open-label, single arm, multicenter long-term extension study of WA19926 (NCT01007435) will evaluate the safety and efficacy of tocilizumab in participants with early, moderate to severe RA who have completed the 104-week WA19926 (NCT01007435) core study. Eligible participants will be those who are expected to benefit from the study medicine based on the investigator's discretion.

Official Title
-----------------
A Multicenter, Open-Label, Single Arm, Long Term Extension Study of WA19926 to Describe Safety During Treatment With Tocilizumab in Patients With Early, Moderate to Severe Rheumatoid Arthritis

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

Intervention / Treatment
-----------------
* Drug: Tocilizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants who completed their last WA19926 (NCT01649804) core study visit (Week 104) and who may benefit from study drug treatment according to the Investigator's assessment No current or recent adverse event or laboratory finding preventing the use of tocilizumab 8 mg/kg at baseline visit Women of childbearing potential must agree to use highly reliable contraception during the treatment period Exclusion Criteria: Pregnant or breastfeeding females Participants who have withdrawn prematurely from the WA19926 (NCT01649804) core study for any reason Treatment with any investigational agent or cell-depleting therapies since the last administration of study drug in WA19926 (NCT01649804) Treatment with an anti-tumor necrosis factor (TNF) or anti-interleukin (IL) 1 agent, or a T-cell costimulation modulator since the last administration of study drug in WA19926 (NCT01649804) Immunization with a live/attenuated vaccine since the last administration of study drug in WA19926 (NCT01649804) Diagnosis since last WA19926 (NCT01649804) visit (Week 104) of rheumatic autoimmune disease other than RA Diagnosis since last WA19926 (NCT01649804) visit (Week 104) of inflammatory joint disease other than RA History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, including tocilizumab and its excipients Evidence of severe uncontrolled concomitant disease or disorder Known active infections or history of recurrent infections Active tuberculosis requiring treatment in the previous 3 years History of alcohol, drug or chemical abuse since inclusion in the WA19926 (NCT01649804) study

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

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

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

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

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 milligrams per kilogram (mg/kg) intravenously (IV) every 4 weeks for up to 104 weeks. | Drug: Tocilizumab<br>* Participants will receive tocilizumab 8 mg/kg IV every 4 weeks for up to 104 weeks.<br>* Other names: RoActemra, Actemra;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with use of study drug, regardless of its relation to study drug. A TEAE is an AE that occurs only once treatment has started. An SAE can be a) fatal, b) life-threatening, c) requires/prolongs hospitalization, d) results in persistent/significant incapacity/disability, e) results in congenital anomaly/birth defect or f) is considered as a significant medical event by the investigator. | Baseline up to approximately 104 weeks | 
| Percentage of Participants With TEAEs of Special Interest | An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with use of study drug, regardless of its relation to study drug. A TEAE is an AE that occurs only once treatment has started. Nine categories of AE of special interest are identified for tocilizumab which includes a) serious/medically significant infections, b) myocardial infarction/acute coronary syndrome, c) gastrointestinal perforations, d) malignancies, e) anaphylaxis/hypersensitivity reactions, f) demyelinating disorders, g) stroke, h) serious and/or medically significant bleeding events, and i) serious/medically significant hepatic events. Data reported is an average of the nine categories. | Baseline up to approximately 104 weeks | 
| Percentage of Participants With TEAEs Leading to Change in Dose or Study Drug Discontinuation | An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with use of study drug, regardless of its relation to study drug. A TEAE is an AE that occurs only once treatment has started. | Baseline up to approximately 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (CFB) in Disease Activity Score 28 Using Erythrocyte Sedimentation Rate (DAS28-ESR) at Specified Time Points | The DAS28-ESR is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen joint counts (SJC) and tender joint counts (TJC), both scored 0-28 (higher scores indicate higher disease activity), as well as acute phase response (APR) determined as erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) (patient global assessment of disease activity [PGA] using visual analog scale [VAS], range 1-100 millimeters [mm]) (higher scores indicate higher disease activity). DAS28-ESR is calculated according to the following formula: DAS28-ESR equals (=) [0.56 multiplied by (*) the square root (√) of TJC] plus (+) [0.28 * √ of SJC] + (0.70 * the natural logarithm [ln] ESR in mm/h) + (0.014*GH in mm VAS). DAS28-ESR scale is transformed and ranges from 0 to 10. A negative CFB indicated improvement. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| CFB in Simplified Disease Activity Index (SDAI) Score at Specified Time Points | The SDAI is a combined index for measuring disease activity. SDAI is the sum of TJC and SJC, both scored 0-28 (higher scores indicate higher disease activity), physician global assessment (PhGA) and PGA of disease activity, both scored 0 to 10 centimeters (cm) as assessed by VAS, and C-reactive protein level (CRP) in milligrams per deciliter (mg/dL) where normal is less than (<) 1 mg/dL. SDAI is calculated according to the following formula: SDAI = TJC + SJC + PhGA + PGA + CRP. SDAI ranges from 0 to 86. A negative CFB indicated improvement. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| CFB in Swollen Joint Count (SJC) at Specified Time Points | For SJC, a total of 66 joints are assessed. The presence of a swollen joint is scored as 1 and absence as 0. Total score is calculated by adding the scores, which ranges from 0 (best possible score or no swollen joint) to 66 (worse possible score or all swollen joints). Lower scores indicated no swollen joint and higher scores indicated worsening swollen joints. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| CFB in Tender Joint Count (TJC) at Specified Time Points | The number of tender joints is recorded on the joint assessment form, no tenderness = 0, tenderness = 1, for 68 joints and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| Percentage of Participants Reaching Clinical Remission (DAS28-ESR Score Less Than [<] 2.6 and/or SDAI Score Less Than or Equal to [</=] 3.3) Among Participants for Whom Tocilizumab Treatment Was Discontinued | Remission: DAS28-ESR score <2.6 and SDAI score </=3.3. DAS28-ESR index included SJC and TJC, both scored 0-28, as well as APR determined as ESR in mm/hr, and GH (ranges 1-100 mm; higher scores=higher disease activity). DAS28=(0.56*√TJC)+(0.28*√SJC) +(0.70*ln ESR) +(0.014*GH). DAS28-ESR scale is transformed and ranges from 0 to 10. Negative CFB indicated improvement. DAS28 >2.6 (clinical remission); DAS28 2.6 to 3.2 (low disease activity); DAS28 >3.2 to 5.1 = moderate to high disease activity. SDAI is sum of TJC and SJC (both scored 0-28), PhGA and PGA of disease activity (both scored 0 to 10 cm as assessed by VAS, higher scores=higher disease activity), and CRP in mg/dL where normal is <1 mg/dL. SDAI=TJC + SJC + PhGA + PGA + CRP. SDAI ranged from 0 to 86. A negative CFB indicated improvement. SDAI <=3.3 (clinical remission), >3.4 to 11 (low disease activity) >11 to 26 (moderate disease activity), and >26 = (high/severe disease activity). | Baseline up to approximately 104 weeks | 
| Time to RA Crisis Among Participants Who Discontinued After Clinical Remission | RA crisis is any worsening of participant disease acitivity that, in the opinion of the investigator, required intensified treatment other than supportive therapy, and may have included restart of the treatment with the study drug. Time to RA crisis is defined as the period of remission without drug until the RA crisis documentation. | Baseline up to approximately 104 weeks | 
| CFB in PGA of Disease Activity Using VAS Score at Specified Time Points | PGA of disease activity is assessed on a 0 to 100 mm horizontal VAS by the participant. 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 CFB indicated improvement. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| CFB in PGA of Pain Using VAS Score at Specified Time Points | PGA of pain is assessed on a 0 to 100 mm horizontal 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, and is described as unbearable pain. A negative change indicated improvement. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| CFB in PhGA of Disease Activity Using VAS Score at Specified Time Points | PhGA of disease activity is assessed on a 0 to 100 mm horizontal 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). | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) | 
| CFB in Health Assessment Questionnaire-Disease Index (HAQ-DI) Score at Specified Time Points | HAQ-DI is a self-reported participant questionnaire specific for RA. It consists of 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. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Total score for HAQ-DI is the sum of all questions and ranges from 0 = without any difficulty to 60 = unable to do. A negative CFB indicates improvement. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks) |