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

Study Overview
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Brief Summary
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This multicenter, open-label, single arm long-term extension of study WA19926 will evaluate the safety and efficacy of tocilizumab (RoActemra/Actemra) in participants with early, moderate to severe rheumatoid arthritis who have completed the WA19926 core study. Eligible participants will receive tocilizumab 8 mg/kg intravenously every 4 weeks for up to 104 weeks.

Official Title
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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
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who complete WA19926 core study (visit at Week 104 and two follow-up telephone visits) 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 the study drug dose of tocilizumab 8 mg/kg at baseline visit Receiving treatment on an outpatient basis Females of child-bearing potential must agree to use at least one adequate method of contraception as defined by protocol during the treatment period Exclusion Criteria: Pregnant women Participants who have prematurely withdrawn from the WA19926 study for any reason Treatment with any investigational agent or cell depleting therapies since last administration of study drug in the WA19926 core study Treatment with an anti-tumor necrosis factor (TNF) or anti-interleukin (IL)1 agent, or a T-cell co-stimulation modulator since the last administration of the study drug in the WA19926 core study Immunization with a live/attenuated vaccine since the last administration of study drug in the WA19926 core study Diagnosis since visit at Week 104 of the core WA19926 study of rheumatic autoimmune disease other than rheumatoid arthritis Diagnosis since visit at Week 104 of the core WA19926 study of inflammatory joint disease other than rheumatoid arthritis Evidence of serious uncontrolled concomitant disease or disorder Known active or history of recurrent infection Current liver disease as determined by Investigator

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 milligrams per kilogram (mg/kg) intravenous infusion every 4 weeks up to 104 weeks. | Drug: Tocilizumab<br>* Tocilizumab will be administered at 8 mg/kg intravenous infusion every 4 weeks, up to 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 |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs), AEs of Special Interest and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs include serious as well as non-serious AEs. AEs of special interest included: Infections including all opportunistic infections and non-serious infections as defined by those treated with IV anti-infectives; Myocardial infarction/acute coronary syndrome; Gastrointestinal perforations and related events; Malignancies; Anaphylaxis/Hypersensitivity reactions; Demyelinating disorders; Stroke; Bleeding events; and Hepatic events. | Baseline up to 112 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Index 28 Erythrocyte Sedimentation Rate (DAS28-ESR) Score | DAS28-ESR was calculated from swollen joint count and tender joint count using 28 joints count, erythrocyte sedimentation rate (ESR, in millimeters per hour [mm/hour]) and patient global assessment (PtGA) of disease activity (participant rated arthritis activity assessment on a 0 to 100 millimeter [mm] visual analog scale [VAS]; higher scores indicating greater affectation due to disease activity). Total DAS28-ESR transformed score range: 0 to approximately 10, higher score=more disease activity. Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from the study for the reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to Week 104) | 
| Change From Baseline in Total Tender Joint Counts (28 Joints) | The number of tender joints was recorded on the joint assessment form, no tenderness = 0, tenderness = 1, for 28 joints and joints were classified as tender/not tender giving a total possible tender joint count of 0 to 28. Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from the study for the reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to Week 104) | 
| Change From Baseline in Total Swollen Joint Counts (28 Joints) | The number of swollen joints was recorded on the joint assessment form, no swelling = 0, swelling =1, for 28 joints and were classified as swollen/not swollen giving a total possible swollen joint count of 0 to 28. Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from the study for the reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to Week 104) | 
| Percentage of Participants With Drug-Free Remission | Drug-free remission was defined as having clinical remission (defined as DAS28-ESR score <2.6) for 2 consecutive assessment visits followed by discontinuation of tocilizumab at the second assessment visit. DAS28-ESR was calculated from swollen joint count and tender joint count using 28 joints count, ESR, (mm/hour) and PtGA of disease activity (participant rated arthritis activity assessment on a 0 to 100 mm VAS; higher scores indicating greater affectation due to disease activity). Total DAS28-ESR transformed score range: 0 to approximately 10, higher score=more disease activity. | Baseline up to Week 104 (assessed at Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit [Week 104], at early withdrawal [up to 104 weeks]) | 
| Percentage of Participants With Clinical Remission | Clinical remission was defined as having DAS28-ESR score <2.6 at any point during the study. DAS28-ESR was calculated from swollen joint count and tender joint count using 28 joints count, ESR, (mm/hour) and PtGA of disease activity (participant rated arthritis activity assessment on a 0 to 100 mm VAS; higher scores indicating greater affectation due to disease activity). Total DAS28-ESR transformed score range: 0 to approximately 10, higher score=more disease activity. | Baseline up to Week 104 (assessed at Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit [Week 104], at early withdrawal [up to 104 weeks]) | 
| Time to Rheumatoid Arthritis (RA) Flare in Participants Who Had Entered Drug-Free Remission | Time to RA flare was defined as the period of drug-free remission (having DAS28-ESR score <2.6 for 2 consecutive assessment visits followed by discontinuation of tocilizumab at the second assessment visit) until documented RA flare. RA flare was defined as any worsening of the participant's disease activity that, in the opinion of the Investigator, required treatment intensification beyond supportive therapy which could include restarting the study drug. | Baseline up to Week 104 (assessed at Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit [Week 104], at early withdrawal [up to 104 weeks]) | 
| Change From Baseline in Physician's Global Assessment (PGA) of Disease Activity Using Visual Analog Scale (VAS) | The PGA of disease activity was assessed using a 0 to 100 mm horizontal VAS by the physician. The left-hand extreme of the line equaled 0 mm, and was described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equaled 100 mm, and was described as maximum disease activity (maximum arthritis disease activity). A negative change from baseline indicated improvement. Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from the study for the reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to 104 weeks) | 
| Change From Baseline in PtGA of Disease Activity Using VAS | The PtGA of disease activity was assessed using a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equaled 0 mm, and was described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equaled 100 mm, and was described as maximum disease activity (maximum arthritis disease activity). A negative change from baseline indicated improvement. Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from the study for the reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to 104 weeks) | 
| Change From Baseline in Participant Assessment of Pain Using VAS | Severity of pain was evaluated by a VAS. Participants marked on a 100 mm horizontal VAS the severity of pain that they had experienced because of their RA, ranging from 0 mm (no pain) to 100 mm (unbearable pain). Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from the study for the reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to 104 weeks) | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) | The HAQ-DI was a participant self-reported questionnaire for assessing the extent of a participant's functional ability. It consisted of 20 questions in 8 categories (dressing and grooming, rising, eating, walking, reach, grip, hygiene, and carrying out daily activities). Each question had 4 response options, ranging from 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. The HAQ-DI scale was an average of all the scores from all questions and ranged from 0 to 3, where higher scores represented higher disease activity. Participants who completed the study, or discontinued the study as per sponsor discretion due to marketing authorization approval, were included in End of Study Visit which was Week 104. Participants who withdrew from study for reason other than sponsor discretion due to marketing authorization approval, were included in Early Withdrawal Visit. Participants with Unspecified reason of discontinuation were excluded for change from baseline analysis. | Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, at end of study visit (Week 104), at early withdrawal (up to 104 weeks) |