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

Primary Purpose

Spondylitis, Ankylosing

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
tocilizumab
Placebo
Sponsored by
Hoffmann-La Roche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spondylitis, Ankylosing

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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  • Traditional disease-modifying anti-rheumatic drugs (DMARDs) must be withdrawn for at least 4 weeks prior to baseline (methotrexate, sulfasalazine and hydroxychloroquine or chloroquine may be allowed if at stable dose for at least 4 weeks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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Experimental

Arm Label

Part 1: Placebo

Part 1: Tocilizumab

Part 2: Placebo

Part 2: Tocilizumab 4 mg/kg

Part 2: Tocilizumab 8 mg/kg

Arm Description

Participants received intravenous infusions of placebo once every 4 weeks until Week 12. Following the Week 12 visit, participants who completed Part 1 of the study received open-label 8 mg/kg tocilizumab through Week 208.

Participants received intravenous infusions of 8 mg/kg tocilizumab once every 4 weeks until Week 12. Following the Week 12 visit, participants who completed Part 1 of the study received open-label 8 mg/kg tocilizumab through Week 208.

Participants received intravenous infusions of placebo once every 4 weeks until Week 24. Participants who did not attain an ASsessment in Ankylosing Spondylitis-20 (ASAS20) response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.

Participants received intravenous infusions of 4 mg/kg tocilizumab once every 4 weeks until Week 24. Participants who did not attain an ASAS20 response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.

Participants received intravenous infusions of 8 mg/kg tocilizumab once every 4 weeks until Week 24. Participants who did not attain an ASAS20 response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.

Outcomes

Primary Outcome Measures

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).
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).

Secondary Outcome Measures

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).
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.
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).
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).
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).
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.
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: Tragus-to-wall; Modified Schober (lumbar flexion); Cervical rotation; Lateral spinal flexion; 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.
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.
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.
Part 2: Peak Plasma Concentration of Tocilizumab
The peak plasma concentration (Cmax) of tocilizumab at steady state after 12 weeks of treatment.
Part 2: Elimination Half-life of Tocilizumab
Elimination half-life of tocilizumab at steady state after 12 weeks of treatment.
Part 2: Clearance of Tocilizumab
Clearance of tocilizumab at steady state after 12 weeks of treatment.
Part 2: Volume of Distribution of Tocilizumab
Volume of distribution of tocilizumab at steady state after 12 weeks of treatment.
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.
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.
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.
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.
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.
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).

Full Information

First Posted
September 24, 2010
Last Updated
January 10, 2013
Sponsor
Hoffmann-La Roche
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1. Study Identification

Unique Protocol Identification Number
NCT01209702
Brief Title
A Study of RoActemra/Actemra (Tocilizumab) in Patients With Ankylosing Spondylitis Who Have Failed Treatment With NSAIDs
Official Title
A Ph II/III Seamless, Multi-center, Randomized, Double-blind, Placebo-controlled Study of the Reduction in Signs and Symptoms and Inhibition of Structural Damage During Treatment With Tocilizumab Versus Placebo in Patients With Ankylosing Spondylitis Who Have Failed Non-steroidal Anti-inflammatory Drugs and Are naïve to TNF Antagonist Therapy NSAIDs
Study Type
Interventional

2. Study Status

Record Verification Date
January 2013
Overall Recruitment Status
Terminated
Why Stopped
Recruitment halted: Failed to achieve efficacy
Study Start Date
September 2010 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spondylitis, Ankylosing

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
306 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received intravenous infusions of placebo once every 4 weeks until Week 12. Following the Week 12 visit, participants who completed Part 1 of the study received open-label 8 mg/kg tocilizumab through Week 208.
Arm Title
Part 1: Tocilizumab
Arm Type
Experimental
Arm Description
Participants received intravenous infusions of 8 mg/kg tocilizumab once every 4 weeks until Week 12. Following the Week 12 visit, participants who completed Part 1 of the study received open-label 8 mg/kg tocilizumab through Week 208.
Arm Title
Part 2: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received intravenous infusions of placebo once every 4 weeks until Week 24. Participants who did not attain an ASsessment in Ankylosing Spondylitis-20 (ASAS20) response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.
Arm Title
Part 2: Tocilizumab 4 mg/kg
Arm Type
Experimental
Arm Description
Participants received intravenous infusions of 4 mg/kg tocilizumab once every 4 weeks until Week 24. Participants who did not attain an ASAS20 response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.
Arm Title
Part 2: Tocilizumab 8 mg/kg
Arm Type
Experimental
Arm Description
Participants received intravenous infusions of 8 mg/kg tocilizumab once every 4 weeks until Week 24. Participants who did not attain an ASAS20 response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.
Intervention Type
Biological
Intervention Name(s)
tocilizumab
Other Intervention Name(s)
RoActemra/Actemra
Intervention Description
Administered intravenously (iv) every 4 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo to tocilizumab administered intravenously every 4 weeks
Primary Outcome Measure Information:
Title
Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
Description
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
Title
Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
Description
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
Secondary Outcome Measure Information:
Title
Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24
Description
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
Title
Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12
Description
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
Title
Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12
Description
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
Title
Part 2: Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 24
Description
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
Title
Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
Description
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
Title
Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI)
Description
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
Title
Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI)
Description
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: Tragus-to-wall; Modified Schober (lumbar flexion); Cervical rotation; Lateral spinal flexion; 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
Title
Change From Baseline in C-Reactive Protein
Description
Levels of C-reactive protein (CRP) were measured from blood samples taken at Baseline and at Week 12.
Time Frame
Baseline and Week 12
Title
Part 2: Area Under the Plasma Concentration Versus Time Curve of Tocilizumab
Description
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).
Title
Part 2: Peak Plasma Concentration of Tocilizumab
Description
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).
Title
Part 2: Elimination Half-life of Tocilizumab
Description
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).
Title
Part 2: Clearance of Tocilizumab
Description
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).
Title
Part 2: Volume of Distribution of Tocilizumab
Description
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).
Title
Change From Baseline in the Level of Interleukin-6
Description
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
Title
Change From Baseline in Level of Soluble Interleukin-6 Receptor
Description
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
Title
Number of Participants With Anti-tocilizumab Antibodies
Description
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).
Title
Part 2: Radiographic Change According to the Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)
Description
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
Title
Part 2: Percentage of Participants With a Reduction of Magnetic Resonance Imaging (MRI) Proven Spinal Inflammation
Description
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
Title
Part 1: The Number of Participants With Adverse Events
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
Huntington Beach
State/Province
California
ZIP/Postal Code
92646
Country
United States
City
Aventura
State/Province
Florida
ZIP/Postal Code
33180
Country
United States
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
City
Decatur
State/Province
Georgia
ZIP/Postal Code
30033
Country
United States
City
Marietta
State/Province
Georgia
ZIP/Postal Code
30060
Country
United States
City
Idaho Falls
State/Province
Idaho
ZIP/Postal Code
83404
Country
United States
City
Wichita
State/Province
Kansas
ZIP/Postal Code
67207
Country
United States
City
Cumberland
State/Province
Maryland
ZIP/Postal Code
21502
Country
United States
City
St. Claire Shores
State/Province
Michigan
ZIP/Postal Code
48081
Country
United States
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28210
Country
United States
City
Greensboro
State/Province
North Carolina
ZIP/Postal Code
27408
Country
United States
City
Duncansville
State/Province
Pennsylvania
ZIP/Postal Code
16635
Country
United States
City
Hickory
State/Province
South Carolina
ZIP/Postal Code
28602
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77004
Country
United States
City
Adelaide
ZIP/Postal Code
5041
Country
Australia
City
Heidelberg
ZIP/Postal Code
3084
Country
Australia
City
Hobart
ZIP/Postal Code
7000
Country
Australia
City
Malvern East
ZIP/Postal Code
3145
Country
Australia
City
Maroochydore
ZIP/Postal Code
4558
Country
Australia
City
Sydney
ZIP/Postal Code
2050
Country
Australia
City
Woodville
ZIP/Postal Code
5011
Country
Australia
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
City
Kortrijk
ZIP/Postal Code
8500
Country
Belgium
City
Liege
ZIP/Postal Code
4000
Country
Belgium
City
Yvoir
ZIP/Postal Code
5530
Country
Belgium
City
Cuiabá
ZIP/Postal Code
78025-000
Country
Brazil
City
Goiania
ZIP/Postal Code
74110-120
Country
Brazil
City
Sao Paulo
ZIP/Postal Code
04026-000
Country
Brazil
City
Sao Paulo
ZIP/Postal Code
04039-000
Country
Brazil
City
São Paulo
ZIP/Postal Code
04266-010
Country
Brazil
City
Plovdiv
ZIP/Postal Code
4002
Country
Bulgaria
City
Plovdiv
ZIP/Postal Code
4003
Country
Bulgaria
City
Ruse
ZIP/Postal Code
7002
Country
Bulgaria
City
Sevlievo
ZIP/Postal Code
5400
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1233
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1606
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1612
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1709
Country
Bulgaria
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 2T9
Country
Canada
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3A 1M3
Country
Canada
City
St John's
State/Province
Newfoundland and Labrador
ZIP/Postal Code
A1C 5B8
Country
Canada
City
Kitchener
State/Province
Ontario
ZIP/Postal Code
N2M 5N6
Country
Canada
City
Mississauga
State/Province
Ontario
ZIP/Postal Code
L5M 2V8
Country
Canada
City
St. Catharines
State/Province
Ontario
ZIP/Postal Code
L2N 7E4
Country
Canada
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M9W 6V1
Country
Canada
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 2M4
Country
Canada
City
Quebec City
State/Province
Quebec
ZIP/Postal Code
G1V 3M7
Country
Canada
City
Sainte-foy
State/Province
Quebec
ZIP/Postal Code
G1W 4R4
Country
Canada
City
Trois-rivieres
State/Province
Quebec
ZIP/Postal Code
G8Z 1Y2
Country
Canada
City
Bruntal
ZIP/Postal Code
792 01
Country
Czech Republic
City
Hlucin
ZIP/Postal Code
748 01
Country
Czech Republic
City
Olomouc
ZIP/Postal Code
775 20
Country
Czech Republic
City
Prague
ZIP/Postal Code
12850
Country
Czech Republic
City
Praha 11
ZIP/Postal Code
148 00
Country
Czech Republic
City
Praha 4 Nusle
ZIP/Postal Code
140 00
Country
Czech Republic
City
Praha 4
ZIP/Postal Code
140 00
Country
Czech Republic
City
Sokolov
ZIP/Postal Code
356 01
Country
Czech Republic
City
Uherske Hradiste
ZIP/Postal Code
686 01
Country
Czech Republic
City
Zlin
ZIP/Postal Code
760 01
Country
Czech Republic
City
Besancon
ZIP/Postal Code
25030
Country
France
City
Boulogne-billancourt
ZIP/Postal Code
92104
Country
France
City
Creteil
ZIP/Postal Code
94010
Country
France
City
Grenoble
ZIP/Postal Code
38042
Country
France
City
Montpellier
ZIP/Postal Code
34295
Country
France
City
Paris
ZIP/Postal Code
75679
Country
France
City
Strasbourg
ZIP/Postal Code
67098
Country
France
City
Toulouse
ZIP/Postal Code
31059
Country
France
City
Berlin
ZIP/Postal Code
10117
Country
Germany
City
Berlin
ZIP/Postal Code
14059
Country
Germany
City
Gommern
ZIP/Postal Code
39245
Country
Germany
City
Hannover
ZIP/Postal Code
30625
Country
Germany
City
Köln
ZIP/Postal Code
50924
Country
Germany
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
City
Ahmedabad
ZIP/Postal Code
380009
Country
India
City
Bangalore
ZIP/Postal Code
560003
Country
India
City
Bangalore
ZIP/Postal Code
560034
Country
India
City
Bangalore
ZIP/Postal Code
560054
Country
India
City
Bangalore
ZIP/Postal Code
560076
Country
India
City
Hyderabad
ZIP/Postal Code
500 033
Country
India
City
Jaipur
ZIP/Postal Code
302 015
Country
India
City
New Delhi
ZIP/Postal Code
110029
Country
India
City
New Delhi
ZIP/Postal Code
110076
Country
India
City
Secunderabad
ZIP/Postal Code
500003
Country
India
City
Ferrara
ZIP/Postal Code
44100
Country
Italy
City
Firenze
ZIP/Postal Code
50141
Country
Italy
City
Monserrato
ZIP/Postal Code
09042
Country
Italy
City
Prato
ZIP/Postal Code
59100
Country
Italy
City
Reggio Emilia
ZIP/Postal Code
42100
Country
Italy
City
Roma
ZIP/Postal Code
00161
Country
Italy
City
Siena
ZIP/Postal Code
53100
Country
Italy
City
Kaunas
ZIP/Postal Code
50009
Country
Lithuania
City
Klaipeda
ZIP/Postal Code
92288
Country
Lithuania
City
Vilnius
ZIP/Postal Code
LT-08661
Country
Lithuania
City
Bydgoszcz
ZIP/Postal Code
85-168
Country
Poland
City
Krakow
ZIP/Postal Code
30-119
Country
Poland
City
Krakow
ZIP/Postal Code
31-121
Country
Poland
City
Lublin
ZIP/Postal Code
20-607
Country
Poland
City
Lublin
ZIP/Postal Code
20-954
Country
Poland
City
Poznan
ZIP/Postal Code
60-218
Country
Poland
City
Torun
ZIP/Postal Code
87-100
Country
Poland
City
Warszawa
ZIP/Postal Code
00-235
Country
Poland
City
Warszawa
ZIP/Postal Code
00-909
Country
Poland
City
Warszawa
ZIP/Postal Code
02-256
Country
Poland
City
Wroclaw
ZIP/Postal Code
51-124
Country
Poland
City
Kazan
ZIP/Postal Code
4420029
Country
Russian Federation
City
Moscow
ZIP/Postal Code
115522
Country
Russian Federation
City
Moscow
ZIP/Postal Code
123060
Country
Russian Federation
City
Voronezh
ZIP/Postal Code
394066
Country
Russian Federation
City
Yaroslavl
ZIP/Postal Code
150062
Country
Russian Federation
City
Kosice
ZIP/Postal Code
040 66
Country
Slovakia
City
Piestany
ZIP/Postal Code
921 01
Country
Slovakia
City
Cape Town
ZIP/Postal Code
7405
Country
South Africa
City
Cape Town
ZIP/Postal Code
7500
Country
South Africa
City
Cape Town
ZIP/Postal Code
8001
Country
South Africa
City
Durban
ZIP/Postal Code
4001
Country
South Africa
City
Pretoria
ZIP/Postal Code
0002
Country
South Africa
City
Pretoria
ZIP/Postal Code
0084
Country
South Africa
City
Pretoria
ZIP/Postal Code
0184
Country
South Africa
City
Stellenbosch
ZIP/Postal Code
7600
Country
South Africa
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
City
Córdoba
ZIP/Postal Code
14004
Country
Spain
City
La Coruna
ZIP/Postal Code
15006
Country
Spain
City
Lugo
ZIP/Postal Code
27004
Country
Spain
City
Madrid
ZIP/Postal Code
28009
Country
Spain
City
Madrid
ZIP/Postal Code
28046
Country
Spain
City
Madrid
ZIP/Postal Code
28222
Country
Spain
City
Oviedo
ZIP/Postal Code
33006
Country
Spain
City
Oviedo
ZIP/Postal Code
33012
Country
Spain
City
Sabadell
ZIP/Postal Code
08208
Country
Spain
City
Basingstoke
ZIP/Postal Code
RG24 9NA
Country
United Kingdom
City
Bath
ZIP/Postal Code
BA1 1RL
Country
United Kingdom
City
Cannock
ZIP/Postal Code
WS11 5XY
Country
United Kingdom
City
Greenock
ZIP/Postal Code
PA16 0XN
Country
United Kingdom
City
Leeds
ZIP/Postal Code
LS7 4SA
Country
United Kingdom
City
London
ZIP/Postal Code
EC1M 6BQ
Country
United Kingdom
City
Salford
ZIP/Postal Code
M6 8HD
Country
United Kingdom
City
Stoke-on-trent
ZIP/Postal Code
ST6 7AG
Country
United Kingdom
City
Wigan
ZIP/Postal Code
WN6 9EW
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
23765873
Citation
Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014 Jan;73(1):95-100. doi: 10.1136/annrheumdis-2013-203559. Epub 2013 Jun 13.
Results Reference
derived

Learn more about this trial

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

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