Spondylitis, Ankylosing
Conditions
Brief summary
This randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of RoActemra/Actemra (tocilizumab) in patients with ankylosing spondylitis (AS) who have failed treatment with non-steroidal anti-inflammatory drugs and are naïve to tumor necrsos factor (TNF) antagonist therapy. In Part 1 of the study, patients will be randomized to receive either RoActemra/Actemra 8 mg/kg intravenously (IV) or placebo every 4 weeks for 12 weeks. In Part 2, patients will be randomized to receive RoActemra at either 8 mg/kg or 4 mg/kg IV or placebo every 4 weeks for 24 weeks. The double-blind treatment period will be followed by open-label treatment with RoActemra/Actemra 8 mg/kg iv every 4 weeks until Week 208 for all patients. Anticipated time on study treatment is 208 weeks.
Detailed description
This study was planned as a Phase II/III seamless, multicenter, randomized, double-blind, placebo-controlled study in patients with AS who were naïve to TNF antagonist therapy. The study consisted of 2 parts, each preceded by a screening visit and followed by a common open-label extension phase. Recruitment into Part 2 commenced after completion of enrollment for Part 1. Part 1 was designed as a Phase II study exploring the efficacy and safety of tocilizumab therapy versus placebo. Part 1 was intended to determine whether Part 2 of the study would continue, based on a Week 12 analysis. Part 2 was designed to provide pivotal Phase III efficacy and safety data for tocilizumab in patients with AS. Approximately 400 patients were to be enrolled. Once randomization into Part 1 was complete, randomization into Part 2 of the study was to be initiated. Based on the results of the Week 12 Part 1 analyses of the primary endpoint (ASAS20) and secondary endpoints, and in consideration of all available safety data, a benefit/risk assessment was made and it was decided to halt the study because of lack of overall efficacy. Most patients did not complete the 24-week double-blind treatment period in Part 2.
Interventions
BIOLOGICALtocilizumab
Administered intravenously (iv) every 4 weeks
DRUGPlacebo
Placebo to tocilizumab administered intravenously every 4 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, ≥ 18 years of age * Ankylosing Spondylitis as defined by the modified New York criteria for ≥ 3 months prior to baseline * Active disease at screening and baseline (Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] ≥4.0, spinal pain visual analog scale \[VAS\] ≥40) * Inadequate response or intolerant to 1 or more previous non-steroidal anti-inflammatory drugs (NSAIDs) * Traditional disease-modifying anti-rheumatic drugs (DMARDs) must be withdrawn for at least 4 weeks prior to baseline (methotrexate, sulfasalazine and hydroxychloroquine or chloroquine may be allowed if at stable dose for at least 4 weeks prior to baseline) * Oral corticosteroids (≥ 10 mg/day prednisone or equivalent) and NSAIDs/COX-2 inhibitors must be at stable dose for at least 4 weeks prior to baseline
Exclusion criteria
* Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months after randomization * Total ankylosis of spine (as determined by investigator) * Inflammatory rheumatic disease other than ankylosing spondylitis * Active, acute uveitis at baseline * Treatment with tumor necrosis factor (TNF) antagonist therapy at any time prior to baseline * Intra-articular or tendon injections or parenteral corticosteroids within 4 weeks prior to screening * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * Active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infection * History of or currently active primary or secondary immunodeficiency * Body weight \> 150 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12 | Baseline and Week 12 | 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). |
| Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12 | Baseline and Week 12 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12 | Week 12 | 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. |
| Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12 | Baseline and Week 12 | 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). |
| Part 2: Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 24 | Baseline and Week 24 | 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). |
| Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Baseline and Week 12 | 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). |
| Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Baseline and Week 12 | 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. |
| Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Baseline and Week 12 | 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. |
| Part 2: Area Under the Plasma Concentration Versus Time Curve of Tocilizumab | Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion). | Area under the plasma concentration versus time curve (AUC) of tocilizumab at steady state after 12 weeks of treatment. |
| Part 2: Peak Plasma Concentration of Tocilizumab | Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion). | The peak plasma concentration (Cmax) of tocilizumab at steady state after 12 weeks of treatment. |
| Change From Baseline in C-Reactive Protein | Baseline and Week 12 | Levels of C-reactive protein (CRP) were measured from blood samples taken at Baseline and at Week 12. |
| Part 2: Clearance of Tocilizumab | Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion). | Clearance of tocilizumab at steady state after 12 weeks of treatment. |
| Part 2: Volume of Distribution of Tocilizumab | Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion). | Volume of distribution of tocilizumab at steady state after 12 weeks of treatment. |
| Change From Baseline in the Level of Interleukin-6 | Baseline and Week 12 | 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. |
| Change From Baseline in Level of Soluble Interleukin-6 Receptor | Baseline and Week 12 | 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. |
| Number of Participants With Anti-tocilizumab Antibodies | From Baseline until end of study (a maximum treatment duration of 40 weeks). | 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. |
| Part 2: Radiographic Change According to the Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) | Baseline and Week 104 | 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. |
| Part 2: Percentage of Participants With a Reduction of Magnetic Resonance Imaging (MRI) Proven Spinal Inflammation | Baseline and Week 24 | 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. |
| Part 1: The Number of Participants With Adverse Events | Up to 40 weeks | 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). |
| Part 2: Elimination Half-life of Tocilizumab | Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion). | Elimination half-life of tocilizumab at steady state after 12 weeks of treatment. |
| Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24 | Baseline and Week 24 | 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). |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, Czechia, France, Germany, India, Italy, Lithuania, Poland, Russia, Slovakia, South Africa, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
In Part 1, patients were randomized in a 1:1 ratio to placebo or tocilizumab (TCZ) 8 mg/kg. In Part 2, patients were randomized in a 2:1:1 ratio to TCZ 8 mg/kg, TCZ 4 mg/kg, or placebo, respectively. Due to the early stopping of the study and limitations in available data the TCZ dose groups in Part 2 were combined.
Participants by arm
| Arm | Count |
|---|---|
| Combined Placebo Participants in Part 1 and Part 2 who received intravenous infusions of placebo once every 4 weeks. | 102 |
| Combined Tocilizumab Participants randomized in Part 1 and Part 2 to receive intravenous infusions of 4 mg/kg (in Part 2 only) or 8 mg/kg tocilizumab once every 4 weeks. | 203 |
| Total | 305 |
Baseline characteristics
| Characteristic | Combined Placebo | Combined Tocilizumab | Total |
|---|---|---|---|
| Age Continuous | 41.2 years STANDARD_DEVIATION 11.33 | 40.4 years STANDARD_DEVIATION 11.42 | 40.7 years STANDARD_DEVIATION 11.38 |
| Age - Part 1 population | 42.7 years STANDARD_DEVIATION 12.64 | 41.6 years STANDARD_DEVIATION 11.22 | 42.1 years STANDARD_DEVIATION 11.91 |
| Gender - Part 1 Population Female | 11 participants | 15 participants | 26 participants |
| Gender - Part 1 Population Male | 40 participants | 36 participants | 76 participants |
| Sex: Female, Male Female | 29 Participants | 53 Participants | 82 Participants |
| Sex: Female, Male Male | 73 Participants | 150 Participants | 223 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 51 | 3 / 51 | 1 / 51 | 8 / 260 |
| serious Total, serious adverse events | 0 / 51 | 2 / 51 | 0 / 51 | 11 / 260 |
Outcome results
Primary
Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
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).
Time frame: Baseline and Week 12
Population: Intent-to-treat (ITT) population included all patients who were randomized into the study and received at least one tocilizumab/placebo infusion.~If the response at the 12-week visit could not be determined due to early withdrawal or missing data then the patient was considered a non-responder.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Placebo | Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12 | 27.5 percentage of participants |
| Part 1: Tocilizumab | Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12 | 37.3 percentage of participants |
Primary
Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
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).
Time frame: Baseline and Week 12
Population: Intent-to-treat (ITT) population. The analysis only includes assessments while the patient was receiving double blind medication, and occurred prior to both withdrawal and the 15 July 2011 (date at which all patients were unblinded). Patients who withdrew or escaped are considered as non-responders until week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Placebo | Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12 | 7.8 percentage of participants |
| Part 1: Tocilizumab | Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12 | 9.2 percentage of participants |
Secondary
Change From Baseline in 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).
Time frame: Baseline and Week 12
Population: Intent-to-treat population where data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Baseline [N=51, 51, 51, 152] | 6.77 cm | Standard Deviation 1.322 |
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Change from Baseline [N=51, 48, 20, 53] | -1.12 cm | Standard Deviation 1.991 |
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Week 12 [N=51, 48, 20, 53] | 5.65 cm | Standard Deviation 2.042 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Baseline [N=51, 51, 51, 152] | 6.62 cm | Standard Deviation 1.327 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Week 12 [N=51, 48, 20, 53] | 5.64 cm | Standard Deviation 1.833 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Change from Baseline [N=51, 48, 20, 53] | -1.02 cm | Standard Deviation 1.813 |
| Part 2: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Baseline [N=51, 51, 51, 152] | 6.86 cm | Standard Deviation 1.506 |
| Part 2: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Change from Baseline [N=51, 48, 20, 53] | -0.53 cm | Standard Deviation 1.637 |
| Part 2: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Week 12 [N=51, 48, 20, 53] | 6.20 cm | Standard Deviation 1.9 |
| Part 2: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Change from Baseline [N=51, 48, 20, 53] | -1.17 cm | Standard Deviation 1.919 |
| Part 2: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Week 12 [N=51, 48, 20, 53] | 5.39 cm | Standard Deviation 2.183 |
| Part 2: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Baseline [N=51, 51, 51, 152] | 6.41 cm | Standard Deviation 1.527 |
Secondary
Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI)
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.
Time frame: Baseline and Week 12
Population: Intent-to-treat population for whom data were available. The analysis was not performed for participants in Part 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Baseline [N=51,51] | 5.60 cm | Standard Deviation 2.071 |
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Week 12 [N=51, 48] | 4.84 cm | Standard Deviation 2.257 |
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Change from Baseline [N=51, 48] | -0.76 cm | Standard Deviation 1.66 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Week 12 [N=51, 48] | 5.55 cm | Standard Deviation 2.004 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Change from Baseline [N=51, 48] | -0.73 cm | Standard Deviation 1.736 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) | Baseline [N=51,51] | 6.24 cm | Standard Deviation 2.069 |
Secondary
Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI)
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.
Time frame: Baseline and Week 12
Population: Intent-to-treat population where data were available. The analysis was not performed for participants in Part 2 due to premature study termination.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Baseline [N=50, 47] | 4.35 scores on a scale | Standard Deviation 1.604 |
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Week 12 [N=50, 47] | 4.29 scores on a scale | Standard Deviation 1.682 |
| Part 1: Placebo | Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Change from Baseline [N=50, 46] | -0.06 scores on a scale | Standard Deviation 0.832 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Baseline [N=50, 47] | 4.58 scores on a scale | Standard Deviation 1.772 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Week 12 [N=50, 47] | 4.40 scores on a scale | Standard Deviation 1.943 |
| Part 1: Tocilizumab | Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) | Change from Baseline [N=50, 46] | -0.21 scores on a scale | Standard Deviation 1.197 |
Secondary
Change From Baseline in C-Reactive Protein
Levels of C-reactive protein (CRP) were measured from blood samples taken at Baseline and at Week 12.
Time frame: Baseline and Week 12
Population: Intent-to-treat population where data were available. The analysis was not performed for participants in Part 2 due to premature study termination.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in C-Reactive Protein | Baseline [N=51, 51] | 1.75 mg/dL | Standard Deviation 1.85 |
| Part 1: Placebo | Change From Baseline in C-Reactive Protein | Week 12 [N=50, 48] | 1.58 mg/dL | Standard Deviation 1.733 |
| Part 1: Placebo | Change From Baseline in C-Reactive Protein | Change from Baseline [N=50, 48] | -0.17 mg/dL | Standard Deviation 1.005 |
| Part 1: Tocilizumab | Change From Baseline in C-Reactive Protein | Change from Baseline [N=50, 48] | -1.34 mg/dL | Standard Deviation 2.442 |
| Part 1: Tocilizumab | Change From Baseline in C-Reactive Protein | Baseline [N=51, 51] | 1.62 mg/dL | Standard Deviation 2.248 |
| Part 1: Tocilizumab | Change From Baseline in C-Reactive Protein | Week 12 [N=50, 48] | 0.36 mg/dL | Standard Deviation 1.008 |
Secondary
Change From Baseline in Level of Soluble Interleukin-6 Receptor
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.
Time frame: Baseline and Week 12
Population: Pharmacokinetic Population: All patients who received at least one tocilizumab infusion and had at least one pharmacokinetic and pharmacodynamic sample. Only those patients with available data at each time point are included in the analysis (indicated by N). Patients who did not receive their week 8 dose were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Level of Soluble Interleukin-6 Receptor | Baseline [N=41] | 42 ng/mL | Standard Deviation 11.5 |
| Part 1: Placebo | Change From Baseline in Level of Soluble Interleukin-6 Receptor | Week 12 [N=40] | 536 ng/mL | Standard Deviation 173.1 |
| Part 1: Placebo | Change From Baseline in Level of Soluble Interleukin-6 Receptor | Change from Baseline [N=37] | 496 ng/mL | Standard Deviation 173.9 |
Secondary
Change From Baseline in the Level of Interleukin-6
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.
Time frame: Baseline and Week 12
Population: Pharmacokinetic (PK) Population: All patients who received at least one tocilizumab infusion and had at least one PK and pharmacodynamic sample. Only patients with available data at each time point are included (indicated by N). Patients who did not receive their Week 8 dose were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in the Level of Interleukin-6 | Baseline [N=41] | 10 pg/mL | Standard Deviation 11.8 |
| Part 1: Placebo | Change From Baseline in the Level of Interleukin-6 | Change from Baseline [N=37] | 67 pg/mL | Standard Deviation 58.3 |
| Part 1: Placebo | Change From Baseline in the Level of Interleukin-6 | Week 12 [N=40] | 78 pg/mL | Standard Deviation 61.5 |
Secondary
Number of Participants With Anti-tocilizumab Antibodies
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.
Time frame: From Baseline until end of study (a maximum treatment duration of 40 weeks).
Population: All patients treated with tocilizumab and screened for anti-tocilizumab antibodies at any timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Anti-tocilizumab Antibodies | 4 participants |
Secondary
Part 1: The Number of Participants With Adverse Events
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).
Time frame: Up to 40 weeks
Population: The safety analysis population included all patients who received at least one tocilizumab/placebo infusion and had at least one postdose safety assessment. Patients were assigned to treatment groups as treated for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Placebo | Part 1: The Number of Participants With Adverse Events | Serious adverse event | 0 participants |
| Part 1: Placebo | Part 1: The Number of Participants With Adverse Events | Withdrawals due to AE | 0 participants |
| Part 1: Placebo | Part 1: The Number of Participants With Adverse Events | Death | 0 participants |
| Part 1: Placebo | Part 1: The Number of Participants With Adverse Events | Severe AE | 0 participants |
| Part 1: Placebo | Part 1: The Number of Participants With Adverse Events | Any adverse event | 27 participants |
| Part 1: Tocilizumab | Part 1: The Number of Participants With Adverse Events | Severe AE | 0 participants |
| Part 1: Tocilizumab | Part 1: The Number of Participants With Adverse Events | Any adverse event | 30 participants |
| Part 1: Tocilizumab | Part 1: The Number of Participants With Adverse Events | Serious adverse event | 2 participants |
| Part 1: Tocilizumab | Part 1: The Number of Participants With Adverse Events | Death | 0 participants |
| Part 1: Tocilizumab | Part 1: The Number of Participants With Adverse Events | Withdrawals due to AE | 0 participants |
Secondary
Part 2: Area Under the Plasma Concentration Versus Time Curve of Tocilizumab
Area under the plasma concentration versus time curve (AUC) of tocilizumab at steady state after 12 weeks of treatment.
Time frame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
Population: Due to premature study termination pharmacokinetic parameters were not analyzed.
Secondary
Part 2: Clearance of Tocilizumab
Clearance of tocilizumab at steady state after 12 weeks of treatment.
Time frame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
Population: Due to premature study termination pharmacokinetic parameters were not analyzed.
Secondary
Part 2: Elimination Half-life of Tocilizumab
Elimination half-life of tocilizumab at steady state after 12 weeks of treatment.
Time frame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
Population: Due to premature study termination pharmacokinetic parameters were not analyzed.
Secondary
Part 2: Peak Plasma Concentration of Tocilizumab
The peak plasma concentration (Cmax) of tocilizumab at steady state after 12 weeks of treatment.
Time frame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
Population: Due to premature study termination pharmacokinetic parameters were not analyzed.
Secondary
Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24
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).
Time frame: Baseline and Week 24
Population: Intent-to-treat (ITT) population. The analysis only includes assessments while the patient was receiving double blind medication, and occurred prior to both withdrawal and the 15 July 2011 (date at which all patients were unblinded). Patients who withdrew or escaped are considered as non-responders until week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Placebo | Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24 | 0.0 percentage of participants |
| Part 1: Tocilizumab | Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24 | 0.0 percentage of participants |
Secondary
Part 2: Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 24
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).
Time frame: Baseline and Week 24
Population: Intent-to-treat (ITT), Part 2 study population. This analysis was not performed due to premature study termination.
Secondary
Part 2: Percentage of Participants With a Reduction of Magnetic Resonance Imaging (MRI) Proven Spinal Inflammation
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.
Time frame: Baseline and Week 24
Population: Due to premature study termination this outcome measure was not analyzed.
Secondary
Part 2: Radiographic Change According to the Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)
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.
Time frame: Baseline and Week 104
Population: This outcome measure was not analyzed due to premature study termination.
Secondary
Part 2: Volume of Distribution of Tocilizumab
Volume of distribution of tocilizumab at steady state after 12 weeks of treatment.
Time frame: Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).
Population: Due to premature study termination pharmacokinetic parameters were not analyzed.
Secondary
Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12
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).
Time frame: Baseline and Week 12
Population: Intent-to-treat (ITT) population. If the response at the Week 12 visit could not be determined due to early withdrawal or missing data then the patient is considered a non-responder. The analysis was not performed for participants in Part 2 due to premature study termination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Placebo | Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12 | 19.6 percentage of participants |
| Part 1: Tocilizumab | Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12 | 11.8 percentage of participants |
Secondary
Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12
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.
Time frame: Week 12
Population: Intent-to-treat. If the response at the Week 12 visit could not be determined due to early withdrawal or missing data then the patient is considered a non-responder. The analysis was not performed for participants in Part 2 due to premature study termination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Placebo | Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12 | 2.0 percentage of participants |
| Part 1: Tocilizumab | Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12 | 0.0 percentage of participants |