A Study of RoActemra/Actemra (Tocilizumab) in Patients With Ankylosing Spondylitis Who Have Failed Treatment With NSAIDs

ASAS is composed of four domains. To achieve an ASAS20 response required improvement of ≥20% and ≥ 1 unit (10 mm) in at least 3 domains and no worsening of ≥ 20 % and ≥ 1 unit (10 mm) in the remaining domain.

• The patient's global assessment of current disease status, measured on a 100 mm visual analog scale (VAS), from symptom-free / no AS symptoms (0) to maximum AS disease severity (100).
• The patient's overall assessment of the severity of spinal pain based on responses to 2 questions assessed on a 100 mm VAS, from no pain (0) to most severe pain (100). The spinal pain score is the mean of these 2 questions.
• The function component was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI). The patient provides self-assessment of 10 questions on a 100 mm VAS. The BASFI score is the mean of these values.
• The inflammation component of the ASAS was determined by the mean of questions 5 and 6 of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

Assessment in Ankylosing Spondylitis (ASAS) is composed of four domains.

• The patient's global assessment of current disease status, measured on a 100 mm visual analog scale (VAS), from symptom-free / no AS symptoms (0) to maximum AS disease severity (100).
• The patient's overall assessment of the severity of spinal pain based on responses to 2 questions assessed on a 100 mm VAS, from no pain (0) to most severe pain (100). The spinal pain score is the mean of these 2 questions.
• The function component was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI), the mean of 10 self-assessment questions on a 100 mm VAS.
• The inflammation component of the ASAS was determined by the mean of questions 5 and 6 of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

Each of the above 4 domains are measured on a scale from 0-100 mm, but reported on a 0-10 cm scale. A score of less than 2 units (20 mm) in each domain is defined as partial remission.

ASAS is composed of four domains. To achieve an ASAS40 response required improvement of ≥40% and ≥ 2 units (20 mm) in at least 3 domains and no worsening at all in the remaining domain.

• The patient's global assessment of current disease status, measured on a 100 mm visual analog scale (VAS), from symptom-free / no AS symptoms (0) to maximum AS disease severity (100).
• The patient's overall assessment of the severity of spinal pain based on responses to 2 questions assessed on a 100 mm VAS, from no pain (0) to most severe pain (100). The spinal pain score is the mean of these 2 questions.
• The function component was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI). The patient provides self-assessment of 10 questions on a 100 mm VAS. The BASFI score is the mean of these values.
• The inflammation component of the ASAS was determined by the mean of questions 5 and 6 of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

ASAS is composed of four domains. To achieve an ASAS40 response required improvement of ≥40% and ≥ 2 units (20 mm) in at least 3 domains and no worsening at all in the remaining domain.

• The patient's global assessment of current disease status, measured on a 100 mm visual analog scale (VAS), from symptom-free / no AS symptoms (0) to maximum AS disease severity (100).
• The patient's overall assessment of the severity of spinal pain based on responses to 2 questions assessed on a 100 mm VAS, from no pain (0) to most severe pain (100). The spinal pain score is the mean of these 2 questions.
• The function component was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI). The patient provides self-assessment of 10 questions on a 100 mm VAS. The BASFI score is the mean of these values.
• The inflammation component of the ASAS was determined by the mean of questions 5 and 6 of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

The BASDAI is a patient-administered assessment of 6 parameters specific to AS. The following parameters were assessed on a 100-mm horizontal visual analogue: fatigue, spinal pain, peripheral arthritis, enthesitis, intensity of morning stiffness, and duration of morning stiffness. For questions 1 to 5, the left-hand extreme of the line (0) represents "none" (symptom-free) and the right-hand extreme (100) represents "very severe" (maximum severity). For question 6, a time axis was used, with the left-hand extreme of the line representing "0 hours" and the right-hand extreme representing "2 or more hours". The BASDAI score was calculated as follows:

BASDAI = [Q1 + Q2 + Q3 + Q4 + (Q5 + Q6)/2]/5. The total score is tabulated on a scale from 0 (best) to 10 cm (worst).

The Bath Ankylosing Spondylitis Functional Index (BASFI) is an assessment of function in AS patients. The participant provides their assessment of their ability to perform 10 activities on a 100 mm horizontal visual analog scale (VAS) ranging from 0 (easy) to 100 (impossible). The BASFI score is the mean of these values and is tabulated on a 0 (best) to 10 (worst) cm scale.

The Bath Ankylosing Spondylitis Metrology Index linear function is a combined index of 5 clinical measurements (performed by the Joint Assessor) which reflect axial mobility in the AS patient. The measurements to assess mobility are:

1. Tragus-to-wall;
2. Modified Schober (lumbar flexion);
3. Cervical rotation;
4. Lateral spinal flexion;
5. Intermalleolar distance.

The BASMI linear result is the average of the 5 assessments and ranges from 0 to 10. The higher the BASMI score the more severe the patient's limitation of movement due to their AS.

Levels of C-reactive protein (CRP) were measured from blood samples taken at Baseline and at Week 12.

Area under the plasma concentration versus time curve (AUC) of tocilizumab at steady state after 12 weeks of treatment.

The peak plasma concentration (Cmax) of tocilizumab at steady state after 12 weeks of treatment.

Elimination half-life of tocilizumab at steady state after 12 weeks of treatment.

Clearance of tocilizumab at steady state after 12 weeks of treatment.

Volume of distribution of tocilizumab at steady state after 12 weeks of treatment.

Interleukin-6 levels were measured from blood samples taken pre-dose at Baseline and after 12 weeks of treatment.

The analysis was not performed for participants in Part 2 due to premature study termination.

Soluble Interleukin-6 receptor levels were measured from blood samples taken pre-dose at Baseline and after 12 weeks of treatment.

The analysis was not performed for participants in Part 2 due to premature study termination.

A positive anti-tocilizumab antibody result was defined as a negative assay result at Baseline and a positive post-baseline screening assay with positive confirmation or neutralizing assay at the same visit.

Radiographs were to be assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The mSASSS is a four-point scoring system for lateral radiographs of the lumbar and cervical spine and has been shown to reliably track disease progression over time, where:

• 0 = No abnormality;
• 1 = Erosion, sclerosis, or squaring;
• 2 = Syndesmophyte;
• 3 = Total bony bridging at each site.

Magentic resonance imaging of the axial skeleton was to be performed at Baseline and Week 24. MRI scans will be evaluated using the ankylosing spondylitis spinal MRI activity (ASspiMRI-a) score, grading activity (0-6) per vertebral unit in 23 units.

A serious adverse event (AE) is any event that is fatal, life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant or requires intervention to prevent one or other of the outcomes listed above. The intensity of each AE was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.02. A severe AE was any event of Grade 4 (life-threatening consequences; urgent intervention indicated) or 5 (death related to AE).