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

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ClinicalTrials.gov Identifier: NCT01163747
Recruitment Status : Completed
First Posted : July 16, 2010
Results First Posted : December 7, 2012
Last Update Posted : December 7, 2012
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Biological: tocilizumab
Drug: methotrexate
Biological: 23-Valent Pneumococcal Polysaccharide Vaccine
Biological: Tetanus Toxoid Adsorbed Vaccine
Enrollment 91

Recruitment Details  
Pre-assignment Details This study was conducted at 35 centers in the United States. Among the 112 patients screened, 91 patients were randomized in a 1:2 ratio to the methotrexate alone or to the tocilizumab + methotrexate treatment group.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 31 60
Per Protocol Population 27 [1] 54 [1]
Completed 25 49
Not Completed 6 11
Reason Not Completed
Adverse Event             0             5
Insufficient Therapeutic Response             0             1
Protocol Violation             0             1
Refused Treatment             6             4
[1]
Participants who received at least 1 dose of study treatment excluding major protocol violators.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 27 54 81
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 27 participants 54 participants 81 participants
51.4  (9.47) 51.1  (8.90) 51.2  (9.04)
[1]
Measure Description: Demographic data are provided for the per protocol population.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 54 participants 81 participants
Female
22
  81.5%
41
  75.9%
63
  77.8%
Male
5
  18.5%
13
  24.1%
18
  22.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 27 participants 54 participants 81 participants
27 54 81
1.Primary Outcome
Title Percentage of Participants Who Responded to ≥ 6 of 12 Anti-pneumococcal Antibody Serotypes
Hide Description

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.

Time Frame Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable per protocol population for pneumococcal polysaccharide vaccine: participants who received at least one dose of study medication, had no major protocol violations, had both baseline (Week 3) and Week 8 assessments of response with evaluable titers to the pneumococcal vaccine.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 24 50
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
70.8
(52.6 to 89.0)
60.0
(46.4 to 73.6)
2.Secondary Outcome
Title Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes
Hide Description

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.

Time Frame Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable per protocol population for pneumococcal polysaccharide vaccine: participants who received at least one dose of study medication, had no major protocol violations, had both baseline (Week 3) and Week 8 assessments of response with evaluable titers to the pneumococcal vaccine.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 24 50
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Responded to ≥1 out of 12 serotypes
87.5
(74.3 to 100.0)
90.0
(81.7 to 98.3)
Responded to ≥2 out of 12 serotypes
87.5
(74.3 to 100.0)
86.0
(76.4 to 95.6)
Responded to ≥3 out of 12 serotypes
83.3
(68.4 to 98.2)
80.0
(68.9 to 91.1)
Responded to ≥4 out of 12 serotypes
83.3
(68.4 to 98.2)
74.0
(61.8 to 86.2)
Responded to ≥5 out of 12 serotypes
83.3
(68.4 to 98.2)
66.0
(52.9 to 79.1)
Responded to ≥6 out of 12 serotypes
70.8
(52.6 to 89.0)
60.0
(46.4 to 73.6)
Responded to ≥7 out of 12 serotypes
58.3
(38.6 to 78.1)
54.0
(40.2 to 67.8)
Responded to ≥8 out of 12 serotypes
58.3
(38.6 to 78.1)
38.0
(24.5 to 51.5)
Responded to ≥9 out of 12 serotypes
45.8
(25.9 to 65.8)
32.0
(19.1 to 44.9)
Responded to ≥10 out of 12 serotypes
29.2
(11.0 to 47.4)
20.0
(8.9 to 31.1)
Responded to ≥ 11 out of 12 serotypes
20.8
(4.6 to 37.1)
12.0
(3.0 to 21.0)
Responded to 12 out of 12 serotypes
8.3
(0.0 to 19.4)
6.0
(0.0 to 12.6)
3.Secondary Outcome
Title Percentage of Participants With a Positive Response to Tetanus Toxoid Vaccination
Hide Description 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.
Time Frame Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable per protocol population for tetanus toxoid vaccine: participants who received at least one dose of study medication, had no major protocol violations, had both baseline (Week 3) and Week 8 assessments of response with evaluable titers to the tetanus toxoid vaccine.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 23 50
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
39.1
(19.2 to 59.1)
42.0
(28.3 to 55.7)
4.Secondary Outcome
Title Change From Baseline in Levels of Anti-pneumococcal Antibody 5 Weeks After Vaccination
Hide Description 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).
Time Frame Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable per protocol population for pneumococcal polysaccharide vaccine: participants who received at least one dose of study medication, had no major protocol violations, had both baseline (Week 3) and Week 8 assessments of response with evaluable titers to the pneumococcal vaccine.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 22 48
Mean (Standard Deviation)
Unit of Measure: mg/L
Baseline 91.1  (122.91) 73.9  (63.50)
Week 8 307.2  (270.25) 184.2  (197.99)
Change from Baseline 216.1  (261.85) 110.2  (188.74)
5.Secondary Outcome
Title Change From Baseline in Levels of Anti-tetanus Antibody 5 Weeks After Vaccination
Hide Description 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).
Time Frame Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable per protocol population for tetanus toxoid vaccine: participants who received at least one dose of study medication, had no major protocol violations, had both baseline (Week 3) and Week 8 assessments of response with evaluable titers to the tetanus toxoid vaccine.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 23 50
Mean (Standard Deviation)
Unit of Measure: IU/mL
Baseline 2  (1.3) 2  (1.9)
Week 8 9  (12.4) 9  (9.2)
Change from Baseline 7  (12.3) 7  (9.0)
6.Secondary Outcome
Title Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes
Hide Description

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.

Time Frame Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable per protocol population for pneumococcal polysaccharide vaccine. N indicates the number of participants with available data for each serotype. No imputation was performed.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 24 50
Measure Type: Number
Unit of Measure: percentage of participants
Serotype 1 response [N=24, 49] 79.2 65.3
Serotype 3 response [N=24, 49] 62.5 53.1
Serotype 4 response [N=24, 50] 33.3 38.0
Serotype 6B response [N=24, 50] 58.3 46.0
Serotype 7F response [N=24, 49] 66.7 61.2
Serotype 8 response [N=24, 49] 75.0 59.2
Serotype 9N response [N=23, 50] 73.9 56.0
Serotype 12F response [N=23, 49] 21.7 26.5
Serotype 14 response [N=21, 50] 57.1 56.0
Serotype 18C response [N=24, 50] 79.2 64.0
Serotype 19F response [N=24, 50] 70.8 54.0
Serotype 23F response [N=24, 50] 50.0 44.0
7.Secondary Outcome
Title Number of Participants With Adverse Events Through Week 8
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment were included in the safety evaluation.
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 31 60
Measure Type: Number
Unit of Measure: participants
Any adverse event 3 23
Serious adverse event 1 2
Deaths 0 0
Withdrawals due to adverse events 0 1
Time Frame From Day 1 through Week 28.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Methotrexate Tocilizumab + Methotrexate
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Methotrexate Tocilizumab + Methotrexate
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Methotrexate Tocilizumab + Methotrexate
Affected / at Risk (%) Affected / at Risk (%)
Total   1/31 (3.23%)   3/60 (5.00%) 
Infections and infestations     
Cellulitis  1  1/31 (3.23%)  1/60 (1.67%) 
Intraspinal abscess  1  0/31 (0.00%)  1/60 (1.67%) 
Staphylococcal sepsis  1  0/31 (0.00%)  1/60 (1.67%) 
Metabolism and nutrition disorders     
Dehydration  1  0/31 (0.00%)  1/60 (1.67%) 
Vascular disorders     
Hypertensive crisis  1  0/31 (0.00%)  1/60 (1.67%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA version 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Methotrexate Tocilizumab + Methotrexate
Affected / at Risk (%) Affected / at Risk (%)
Total   9/31 (29.03%)   25/60 (41.67%) 
Gastrointestinal disorders     
Nausea  1  1/31 (3.23%)  4/60 (6.67%) 
Infections and infestations     
Upper respiratory tract infection  1  3/31 (9.68%)  4/60 (6.67%) 
Sinusitis  1  1/31 (3.23%)  5/60 (8.33%) 
Nasopharyngitis  1  2/31 (6.45%)  3/60 (5.00%) 
Urinary tract infection  1  2/31 (6.45%)  2/60 (3.33%) 
Bronchitis  1  0/31 (0.00%)  3/60 (5.00%) 
Nervous system disorders     
Headache  1  0/31 (0.00%)  4/60 (6.67%) 
Psychiatric disorders     
Anxiety  1  0/31 (0.00%)  3/60 (5.00%) 
Skin and subcutaneous tissue disorders     
Rash  1  0/31 (0.00%)  3/60 (5.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA version 15.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title: Medical Communications
Organization: Hoffman-LaRoche
Phone: 800-821-8590
Publications of Results:
Bingham III C.O, Rizzo W, Klearman M, et al. Preliminary results from a controlled trial (VISARA) to evaluate the humoural immune response to vaccines in RA patients treated with tocilizumab (TCZ). Ann Rheum Dis. 2012;71(Suppl 3):345.
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01163747     History of Changes
Other Study ID Numbers: NA25256
First Submitted: July 14, 2010
First Posted: July 16, 2010
Results First Submitted: November 12, 2012
Results First Posted: December 7, 2012
Last Update Posted: December 7, 2012