Spondylitis, Ankylosing
Conditions
Brief summary
This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of tocilizumab (RoActemra/Actemra) in patients with ankylosing spondylitis (AS) who had an inadequate response to previous tumor necrosis factor (TNF) antagonist therapy. Patients were randomized to receive tocilizumab at a dose of either 8 mg/kg or 4 mg/kg intravenously (iv) or placebo every 4 weeks for 24 weeks. The double-blind treatment period was followed by open-label treatment with tocilizumab 8 mg/kg iv every 4 weeks until Week 104 for all patients. This study and all further clinical development of tocilizumab AS was halted after a review of 12-week data from Study NA22823, a randomized double-blind, placebo-controlled study in TNF antagonist naïve AS patients, failed to demonstrate efficacy.
Interventions
DRUGTocilizumab
DRUGPlacebo
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). * Inadequate response to treatment with etanercept, infliximab, adalimumab, or golimumab because of inadequate efficacy. * Tumor necrosis factor (TNF) antagonist therapy must have been discontinued at least 8 weeks prior to baseline (etanercept 4 weeks). * Traditional disease-modifying anti-rheumatic drugs (DMARDs) must be withdrawn for at least 4 weeks prior to baseline (methotrexate, sulfasalazine, and hydroxychloroquine or chloroquine may be allowed if at stable dose for at least 4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/cyclooxygenase-2 \[COX-2\] 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. * Previous treatment with tocilizumab. * 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 |
|---|---|---|
| Percentage of ASsessment in Ankylosing Spondylitis 20 (ASAS20) Responders at Week 12 | Baseline to Week 12 | ASAS20 was defined as an improvement of ≥ 20% and an absolute improvement of ≥ 10 units on a 0-100 visual analog scale (VAS) from Baseline to Week 12 in 3 of 4 domains: 1-Patient global assessment (with extremes labelled none and severe), 2-Pain assessment (average total and nocturnal pain scores with extremes labelled no pain and most severe pain), 3-Function (represented by the Bath Ankylosing Spondylitis (BAS) Functional Index \[BASFI\] average of 10 questions regarding ability to perform specific tasks with extremes labelled easy and impossible), and 4-Inflammation (average of the last 2 questions on the 6-question BAS Disease Activity Index \[BASDAI\] concerning morning stiffness intensity with extremes labelled none and very severe and duration between 0 and 2 or more hours); and the absence of deterioration (of at least 20% and absolute change of at least 10 units on a 0-100 mm scale) in the remaining domain. |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, Czechia, Denmark, France, Germany, India, Italy, Lithuania, Netherlands, Poland, Slovakia, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
Because of the early termination of the study and the limited and varying duration of treatment, the 4 mg/kg and 8 mg/kg tocilizumab dose groups were combined in the efficacy and safety analyses and reporting.
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab 4 or 8 mg/kg Patients received tocilizumab 4 or 8 mg/kg intravenously every 4 weeks for 24 weeks. | 91 |
| Placebo Patients received placebo to tocilizumab intravenously every 4 weeks for 24 weeks. | 22 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Failure to Return | 3 | 0 |
| Overall Study | Insufficient Therapeutic Response | 7 | 2 |
| Overall Study | Refused Treatment | 8 | 3 |
| Overall Study | Sponsor's Decision to Stop the Study | 68 | 17 |
| Overall Study | Violation of Selection Criteria at Entry | 1 | 0 |
Baseline characteristics
| Characteristic | Tocilizumab 4 or 8 mg/kg | Placebo | Total |
|---|---|---|---|
| Age Continuous | 44.1 years STANDARD_DEVIATION 12.08 | 45.0 years STANDARD_DEVIATION 12.66 | 44.3 years STANDARD_DEVIATION 12.14 |
| Sex: Female, Male Female | 29 Participants | 8 Participants | 37 Participants |
| Sex: Female, Male Male | 62 Participants | 14 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 95 | 1 / 22 |
| serious Total, serious adverse events | 6 / 95 | 0 / 22 |
Outcome results
Primary
Percentage of ASsessment in Ankylosing Spondylitis 20 (ASAS20) Responders at Week 12
ASAS20 was defined as an improvement of ≥ 20% and an absolute improvement of ≥ 10 units on a 0-100 visual analog scale (VAS) from Baseline to Week 12 in 3 of 4 domains: 1-Patient global assessment (with extremes labelled none and severe), 2-Pain assessment (average total and nocturnal pain scores with extremes labelled no pain and most severe pain), 3-Function (represented by the Bath Ankylosing Spondylitis (BAS) Functional Index \[BASFI\] average of 10 questions regarding ability to perform specific tasks with extremes labelled easy and impossible), and 4-Inflammation (average of the last 2 questions on the 6-question BAS Disease Activity Index \[BASDAI\] concerning morning stiffness intensity with extremes labelled none and very severe and duration between 0 and 2 or more hours); and the absence of deterioration (of at least 20% and absolute change of at least 10 units on a 0-100 mm scale) in the remaining domain.
Time frame: Baseline to Week 12
Population: Intent-to-treat population: All randomized patients who received at least 1 dose of treatment. The analysis only included assessments while patients were receiving double-blind treatment and that occurred prior to withdrawal or the date when all patients were unblinded (15 Jul 2011). Patients who withdrew or escaped were considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab 4 or 8 mg/kg | Percentage of ASsessment in Ankylosing Spondylitis 20 (ASAS20) Responders at Week 12 | 12.7 Percentage of patients |
| Placebo | Percentage of ASsessment in Ankylosing Spondylitis 20 (ASAS20) Responders at Week 12 | 14.3 Percentage of patients |