A Study of the Effects of RoActemra/Actemra on Vaccination in Patients With Rheumatoid Arthritis on Background Methotrexate (VISARA)

Study Overview
=================
Brief Summary
-----------------
This randomized, parallel-group, open-label study will evaluate the effect of Actemra (tocilizumab) on vaccination in patients with active rheumatoid arthritis who have an inadequate response to methotrexate and who have had an inadequate clinical response or were intolerant to treatment with one or more anti-tumor necrosis factor (anti-TNF) therapies.

Official Title
-----------------
A Randomized, Parallel-group, Open-label, Multicenter Study to Evaluate the Effects of Tocilizumab on Vaccination in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Biological: tocilizumab
* Drug: methotrexate
* Biological: 23-Valent Pneumococcal Polysaccharide Vaccine
* Biological: Tetanus Toxoid Adsorbed Vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients, ≥ 18 to < 65 years of age Rheumatoid Arthritis (RA) of > 6 months duration at baseline (American College of Rheumatology criteria) Willing to receive immunization with pneumococcal polysaccharide and tetanus toxoid adsorbed vaccines Previous immunization with pneumococcal polysaccharide must have occurred ≥ 3 years of baseline, with tetanus containing vaccine ≥ 5 years Methotrexate therapy for at least 8 weeks prior to baseline at stable dose of 7.5-25 mg/week (oral or parenteral) Other disease-modifying antirheumatic drugs (DMARDs) must be withdrawn before baseline Oral corticosteroids must be at stable dose of < 10 mg/day prednisone or equivalent Body weight ≤ 150 kg at screening Exclusion Criteria: Major surgery (including joint surgery) within 12 weeks prior to baseline or planned major surgery within 8 weeks after baseline History of or current inflammatory joint disease or rheumatic autoimmune disease other than RA Pre-existing central nervous system demyelinating or seizure disorders Active current or history of recurrent bacterial, viral fungal, mycobacterial and other infections Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to baseline or oral antibiotics within 2 weeks prior to baseline Active tuberculosis requiring treatment within 3 years prior to baseline Primary or secondary immunodeficiency (history or currently active) Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline Previous treatment with RoActemra/Actemra

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methotrexate<br>Participants continued to receive their standard dose of methotrexate up to Week 8. From Week 8 participants also received 8 mg/kg tocilizumab intravenously every 4 weeks until Week 20. At Week 3 participants received both pneumococcal and tetanus toxoid vaccinations. | Biological: tocilizumab<br>* Intravenous repeating dose<br>* Other names: Actemra;Drug: methotrexate<br>* A stable dose of between 7.5 and 25 mg/week, oral or parenteral.<br>Biological: 23-Valent Pneumococcal Polysaccharide Vaccine<br>* Intramuscular or subcutaneous injection<br>* Other names: Pneumovax;Biological: Tetanus Toxoid Adsorbed Vaccine<br>* Intramuscular injection<br>|
| Experimental: Tocilizumab + Methotrexate<br>Participants received 8 mg/kg tocilizumab intravenously at Baseline (Day 1) and every 4 weeks up to Week 20, in addition to their standard dose of methotrexate. At Week 3 participants received both pneumococcal and tetanus toxoid vaccinations. | Biological: tocilizumab<br>* Intravenous repeating dose<br>* Other names: Actemra;Drug: methotrexate<br>* A stable dose of between 7.5 and 25 mg/week, oral or parenteral.<br>Biological: 23-Valent Pneumococcal Polysaccharide Vaccine<br>* Intramuscular or subcutaneous injection<br>* Other names: Pneumovax;Biological: Tetanus Toxoid Adsorbed Vaccine<br>* Intramuscular injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Responded to ≥ 6 of 12 Anti-pneumococcal Antibody Serotypes | Serum levels of antibody to pneumococcal vaccine were drawn 5 weeks after vaccination with 23-valent pneumococcal polysaccharide vaccine to assess humoral immune response. A positive response to the pneumococcal vaccine was defined as a 2-fold increase in serum antibody titers from Baseline or an increase of > 1 mg/L from Baseline levels. The 12 serotypes evaluated were pneumococcal serotypes 1, 3, 4, 6B, 8, 9N, 12F, 14, 19F, 23F, 7F, and 18C. | Baseline (Week 3) and Week 8 (5 weeks post-vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes | Serum levels of antibody to pneumococcal vaccine were drawn 5 weeks after vaccination with 23-valent pneumococcal polysaccharide vaccine to assess humoral immune response. A positive response to the pneumococcal vaccine was defined as a 2-fold increase in serum antibody titers from Baseline or an increase of > 1 mg/L from Baseline levels. The 12 serotypes evaluated were pneumococcal serotypes 1, 3, 4, 6B, 8, 9N, 12F, 14, 19F, 23F, 7F, and 18C. | Baseline (Week 3) and Week 8 (5 weeks post-vaccination) | 
| Percentage of Participants With a Positive Response to Tetanus Toxoid Vaccination | A positive response to the tetanus toxoid vaccination was defined as antibody levels ≥ 0.2 IU/mL for participants with Baseline tetanus antibody levels < 0.1 IU/mL, or a 4-fold increase in antibody levels compared with Baseline for participants with Baseline tetanus antibody levels ≥ 0.1 IU/mL. | Baseline (Week 3) and Week 8 (5 weeks post-vaccination) | 
| Change From Baseline in Levels of Anti-pneumococcal Antibody 5 Weeks After Vaccination | Levels of anti-pneumococcal antibodies were measured by a central laboratory from serum samples taken prior to vaccination (Week 3) and 5 weeks post vaccination (Week 8). | Baseline (Week 3) and Week 8 (5 weeks post-vaccination) | 
| Change From Baseline in Levels of Anti-tetanus Antibody 5 Weeks After Vaccination | Levels of anti-tetanus antibodies were measured by a central laboratory from serum samples taken prior to vaccination (Week 3) and 5 weeks post vaccination (Week 8). | Baseline (Week 3) and Week 8 (5 weeks post-vaccination) | 
| Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes | Serum levels of antibody to pneumococcal vaccine were drawn 5 weeks after vaccination with 23-valent pneumococcal polysaccharide vaccine to assess humoral immune response. A positive response to the pneumococcal vaccine was defined as a 2-fold increase in serum antibody titers from Baseline or an increase of > 1 mg/L from Baseline levels. The 12 serotypes evaluated were pneumococcal serotypes 1, 3, 4, 6B, 7F, 8, 9N, 12F, 14, 18C, 19F and 23F. | Baseline (Week 3) and Week 8 (5 weeks post-vaccination) | 
| Number of Participants With Adverse Events Through Week 8 | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A Serious Adverse Event (SAE) is any AE that is fatal or is 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. | 8 weeks |