A Study Of Tocilizumab in Patients With Moderate to Severe Active Rheumatoid Arthritis Who Have an Inadequate Response to or Are Unable to Tolerate Biologic and Non-Biologic Disease-modifying Antirheumatic Drugs (DMARDs)

An SAE was any adverse event that at any dose fulfilled at least one of the following criteria:

• Was fatal (results in death)
• Was life-threatening
• Required in-patient hospitalization or prolongation of existing hospitalization
• Resulted in persistent or significant disability/incapacity
• Was a congenital anomaly/birth defect
• Was medically significant or required intervention to prevent one or other of the outcomes listed above.

Serious Adverse Events of Special interest include:

• Serious infections including opportunistic infections
• Complications of diverticulitis (including lower gastrointestinal [GI] perforations)
• Myocardial infarction/acute coronary syndrome
• Stroke
• Spontaneous or serious bleeding
• Malignant neoplasms

Non-serious adverse Events of Special interest include:

• Serious/Medically Significant Hepatic Events
• Spontaneous /Serious Bleeding
• Malignant Neoplasms

Clinical Remission is defined as a Disease Activity Score 28 [DAS28] < 2.6. The DAS28 is a combined index for measuring disease activity in RA. The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.

The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response C-reactive protein (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of < 2.6 represents clinical remission, a score of ≤ 3.2 represents low disease activity, and a score of > 5.1 represents high disease activity.

The Change from Baseline to Weeks 8, 16 and 24 is reported.

The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50%, and ≥70% improvement from baseline, respectively, in:

• Swollen Joint Count (66 joints) and Tender Joint Count (68 joints) and
• At least 3 of the following 5 assessments:

• Patient's global assessment of pain-Visual Analog Scale (VAS)
• Patient global assessment of disease activity-(VAS)
• Physician global assessment of disease activity-(VAS)
• Patient assessment of disability (physical function scale of the Multidimensional Health Assessment Questionnaire)
• Acute phase response C-Reactive Protein (CRP)

Dosage could be increased from 4 mg/kg Tocilizumab to 8 mg/kg due to failure to achieve 20% improvement from baseline in swollen and tender joint counts.

Dosage of Tocilizumab 4 mg/kg could be increased to 8 mg/kg at the discretion of the investigator based on assessment of the patient's benefit-risk after Week 12.

The RAPID3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain Visual Analog Scale (VAS), and global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 10 where higher scores represent worse outcomes. A negative change from baseline indicates improvement.

The fatigue VAS is a single-item, patient-reported outcome that measures the severity of the fatigue over the past week. Patients rate their fatigue on a scale of 0 (fatigue is no problem) to 100 (fatigue is a major problem). Higher scores represent higher disease activity and a negative change from baseline indicates improvement.