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

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Biological: tocilizumab; Drug: methotrexate; Biological: 23-Valent Pneumococcal Polysaccharide Vaccine; Biological: Tetanus Toxoid Adsorbed Vaccine

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
    • Birmingham, Alabama, United States, 35294
    • Huntsville, Alabama, United States, 35801
  • Arizona
    • Glendale, Arizona, United States, 85304
    • Mesa, Arizona, United States, 85202
    • Paradise Valley, Arizona, United States, 85253
    • Paradise Valley, Arizona, United States, 85037
    • Scottsdale, Arizona, United States, 85258
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
  • California
    • Fullerton, California, United States, 92835
    • Hemet, California, United States, 92543
    • San Leandro, California, United States, 94578
    • Santa Maria, California, United States, 93454
    • Upland, California, United States, 91786
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
  • Florida
    • Melbourne, Florida, United States, 32901
    • South Miami, Florida, United States, 33143
    • Tavares, Florida, United States, 32778
  • Idaho
    • Boise, Idaho, United States, 83702
    • Idaho Falls, Idaho, United States, 83404
  • Illinois
    • Maywood, Illinois, United States, 60153
    • Vernon Hills, Illinois, United States, 60061
  • Indiana
    • South Bend, Indiana, United States, 46601
  • Maryland
    • Baltimore, Maryland, United States, 21224
    • Baltimore, Maryland, United States, 21286
  • Michigan
    • Saint Clair Shores, Michigan, United States, 48080
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
  • Nevada
    • Las Vegas, Nevada, United States, 89128
  • New Jersey
    • Manalapan, New Jersey, United States, 07726
  • New York
    • Albany, New York, United States, 12206
  • North Carolina
    • Belmont, North Carolina, United States, 28012
    • Charlotte, North Carolina, United States, 28210
    • Greenville, North Carolina, United States, 27834
  • Ohio
    • Cleveland, Ohio, United States, 44109
    • Gallipolis, Ohio, United States, 45631
    • Middleburg Heights, Ohio, United States, 44130
  • Oregon
    • Lake Oswego, Oregon, United States, 97035
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
    • Philadelphia, Pennsylvania, United States, 19152
    • Wexford, Pennsylvania, United States, 15090
    • Wyomissing, Pennsylvania, United States, 19610
  • South Carolina
    • Charleston, South Carolina, United States, 29407
    • Orangeburg, South Carolina, United States, 29118
  • Texas
    • Dallas, Texas, United States, 75246
    • Mesquite, Texas, United States, 75150
  • Washington
    • Tacoma, Washington, United States, 98405
  • West Virginia
    • Clarksburg, West Virginia, United States, 26301

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methotrexate; 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; Intravenous repeating dose; Other Names: RoActemra; Actemra; Drug: methotrexate; A stable dose of between 7.5 and 25 mg/week, oral or parenteral.; Biological: 23-Valent Pneumococcal Polysaccharide Vaccine; Intramuscular or subcutaneous injection; Other Names: Pneumovax; Biological: Tetanus Toxoid Adsorbed Vaccine; Intramuscular injection
Experimental: Tocilizumab + Methotrexate; 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; Intravenous repeating dose; Other Names: RoActemra; Actemra; Drug: methotrexate; A stable dose of between 7.5 and 25 mg/week, oral or parenteral.; Biological: 23-Valent Pneumococcal Polysaccharide Vaccine; Intramuscular or subcutaneous injection; Other Names: Pneumovax; Biological: Tetanus Toxoid Adsorbed Vaccine; Intramuscular injection

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

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Micki Klearman, M.D., Genentech, Inc.

Publications and helpful links

General Publications

• Bingham CO 3rd, Rizzo W, Kivitz A, Hassanali A, Upmanyu R, Klearman M. Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA). Ann Rheum Dis. 2015 May;74(5):818-22. doi: 10.1136/annrheumdis-2013-204427. Epub 2014 Jan 21.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: July 14, 2010
• First Submitted That Met QC Criteria: July 14, 2010
• First Posted (Estimate): July 16, 2010

Study Record Updates

• Last Update Posted (Estimate): December 7, 2012
• Last Update Submitted That Met QC Criteria: November 12, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine; Methotrexate
• Other Study ID Numbers: NA25256