Trial Outcomes & Findings for A Study of the Effects of RoActemra/Actemra on Vaccination in Patients With Rheumatoid Arthritis on Background Methotrexate (VISARA) (NCT NCT01163747)

NCT ID: NCT01163747

Last Updated: 2012-12-07

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 91 participants
• Primary outcome timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)
• Results posted on: 2012-12-07

Participant Flow

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.

Participant milestones

Measure	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.	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.
Overall Study STARTED	31	60
Overall Study Per Protocol Population	27	54
Overall Study COMPLETED	25	49
Overall Study NOT COMPLETED	6	11

Reasons for withdrawal

Measure	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.	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.
Overall Study Adverse Event	0	5
Overall Study Insufficient Therapeutic Response	0	1
Overall Study Protocol Violation	0	1
Overall Study Refused Treatment	6	4

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Methotrexate n=27 Participants 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.	Tocilizumab + Methotrexate n=54 Participants 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 n=81 Participants Total of all reporting groups
Age Continuous	51.4 years STANDARD_DEVIATION 9.47 • n=5 Participants	51.1 years STANDARD_DEVIATION 8.90 • n=7 Participants	51.2 years STANDARD_DEVIATION 9.04 • n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	41 Participants n=7 Participants	63 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	13 Participants n=7 Participants	18 Participants n=5 Participants
Region of Enrollment United States	27 participants n=5 Participants	54 participants n=7 Participants	81 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)

Population: 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.

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.

Outcome measures

Measure	Methotrexate n=24 Participants 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.	Tocilizumab + Methotrexate n=50 Participants 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.
Percentage of Participants Who Responded to ≥ 6 of 12 Anti-pneumococcal Antibody Serotypes	70.8 percentage of participants Interval 52.6 to 89.0	60.0 percentage of participants Interval 46.4 to 73.6

SECONDARY outcome

Timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)

Population: 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.

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.

Outcome measures

Measure	Methotrexate n=24 Participants 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.	Tocilizumab + Methotrexate n=50 Participants 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.
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥1 out of 12 serotypes	87.5 percentage of participants Interval 74.3 to 100.0	90.0 percentage of participants Interval 81.7 to 98.3
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥2 out of 12 serotypes	87.5 percentage of participants Interval 74.3 to 100.0	86.0 percentage of participants Interval 76.4 to 95.6
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥10 out of 12 serotypes	29.2 percentage of participants Interval 11.0 to 47.4	20.0 percentage of participants Interval 8.9 to 31.1
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥3 out of 12 serotypes	83.3 percentage of participants Interval 68.4 to 98.2	80.0 percentage of participants Interval 68.9 to 91.1
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥4 out of 12 serotypes	83.3 percentage of participants Interval 68.4 to 98.2	74.0 percentage of participants Interval 61.8 to 86.2
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥5 out of 12 serotypes	83.3 percentage of participants Interval 68.4 to 98.2	66.0 percentage of participants Interval 52.9 to 79.1
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥6 out of 12 serotypes	70.8 percentage of participants Interval 52.6 to 89.0	60.0 percentage of participants Interval 46.4 to 73.6
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥7 out of 12 serotypes	58.3 percentage of participants Interval 38.6 to 78.1	54.0 percentage of participants Interval 40.2 to 67.8
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥8 out of 12 serotypes	58.3 percentage of participants Interval 38.6 to 78.1	38.0 percentage of participants Interval 24.5 to 51.5
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥9 out of 12 serotypes	45.8 percentage of participants Interval 25.9 to 65.8	32.0 percentage of participants Interval 19.1 to 44.9
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to ≥ 11 out of 12 serotypes	20.8 percentage of participants Interval 4.6 to 37.1	12.0 percentage of participants Interval 3.0 to 21.0
Percentage of Participants Who Responded to Combinations of 12 Anti-Pneumococcal Antibody Serotypes Responded to 12 out of 12 serotypes	8.3 percentage of participants Interval 0.0 to 19.4	6.0 percentage of participants Interval 0.0 to 12.6

SECONDARY outcome

Timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)

Population: 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.

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.

Outcome measures

Measure	Methotrexate n=23 Participants 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.	Tocilizumab + Methotrexate n=50 Participants 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.
Percentage of Participants With a Positive Response to Tetanus Toxoid Vaccination	39.1 percentage of participants Interval 19.2 to 59.1	42.0 percentage of participants Interval 28.3 to 55.7

SECONDARY outcome

Timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)

Population: 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.

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).

Outcome measures

Measure	Methotrexate n=22 Participants 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.	Tocilizumab + Methotrexate n=48 Participants 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.
Change From Baseline in Levels of Anti-pneumococcal Antibody 5 Weeks After Vaccination Baseline	91.1 mg/L Standard Deviation 122.91	73.9 mg/L Standard Deviation 63.50
Change From Baseline in Levels of Anti-pneumococcal Antibody 5 Weeks After Vaccination Week 8	307.2 mg/L Standard Deviation 270.25	184.2 mg/L Standard Deviation 197.99
Change From Baseline in Levels of Anti-pneumococcal Antibody 5 Weeks After Vaccination Change from Baseline	216.1 mg/L Standard Deviation 261.85	110.2 mg/L Standard Deviation 188.74

SECONDARY outcome

Timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)

Population: 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.

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).

Outcome measures

Measure	Methotrexate n=23 Participants 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.	Tocilizumab + Methotrexate n=50 Participants 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.
Change From Baseline in Levels of Anti-tetanus Antibody 5 Weeks After Vaccination Baseline	2 IU/mL Standard Deviation 1.3	2 IU/mL Standard Deviation 1.9
Change From Baseline in Levels of Anti-tetanus Antibody 5 Weeks After Vaccination Week 8	9 IU/mL Standard Deviation 12.4	9 IU/mL Standard Deviation 9.2
Change From Baseline in Levels of Anti-tetanus Antibody 5 Weeks After Vaccination Change from Baseline	7 IU/mL Standard Deviation 12.3	7 IU/mL Standard Deviation 9.0

SECONDARY outcome

Timeframe: Baseline (Week 3) and Week 8 (5 weeks post-vaccination)

Population: Evaluable per protocol population for pneumococcal polysaccharide vaccine. N indicates the number of participants with available data for each serotype. No imputation was performed.

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.

Outcome measures

Measure	Methotrexate n=24 Participants 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.	Tocilizumab + Methotrexate n=50 Participants 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.
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 12F response [N=23, 49]	21.7 percentage of participants	26.5 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 14 response [N=21, 50]	57.1 percentage of participants	56.0 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 1 response [N=24, 49]	79.2 percentage of participants	65.3 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 3 response [N=24, 49]	62.5 percentage of participants	53.1 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 4 response [N=24, 50]	33.3 percentage of participants	38.0 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 6B response [N=24, 50]	58.3 percentage of participants	46.0 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 7F response [N=24, 49]	66.7 percentage of participants	61.2 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 8 response [N=24, 49]	75.0 percentage of participants	59.2 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 9N response [N=23, 50]	73.9 percentage of participants	56.0 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 18C response [N=24, 50]	79.2 percentage of participants	64.0 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 19F response [N=24, 50]	70.8 percentage of participants	54.0 percentage of participants
Percentage of Participants Who Responded to Each of the 12 Anti-Pneumococcal Antibody Serotypes Serotype 23F response [N=24, 50]	50.0 percentage of participants	44.0 percentage of participants

SECONDARY outcome

Timeframe: 8 weeks

Population: All participants who received at least one dose of study treatment were included in the safety evaluation.

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.

Outcome measures

Measure	Methotrexate n=31 Participants 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.	Tocilizumab + Methotrexate n=60 Participants 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.
Number of Participants With Adverse Events Through Week 8 Any adverse event	3 participants	23 participants
Number of Participants With Adverse Events Through Week 8 Serious adverse event	1 participants	2 participants
Number of Participants With Adverse Events Through Week 8 Deaths	0 participants	0 participants
Number of Participants With Adverse Events Through Week 8 Withdrawals due to adverse events	0 participants	1 participants

Adverse Events

Methotrexate

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Tocilizumab + Methotrexate

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Measure	Methotrexate n=31 participants at risk 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.	Tocilizumab + Methotrexate n=60 participants at risk 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.
Infections and infestations Cellulitis	3.2% 1/31 • From Day 1 through Week 28.	1.7% 1/60 • From Day 1 through Week 28.
Infections and infestations Intraspinal abscess	0.00% 0/31 • From Day 1 through Week 28.	1.7% 1/60 • From Day 1 through Week 28.
Infections and infestations Staphylococcal sepsis	0.00% 0/31 • From Day 1 through Week 28.	1.7% 1/60 • From Day 1 through Week 28.
Metabolism and nutrition disorders Dehydration	0.00% 0/31 • From Day 1 through Week 28.	1.7% 1/60 • From Day 1 through Week 28.
Vascular disorders Hypertensive crisis	0.00% 0/31 • From Day 1 through Week 28.	1.7% 1/60 • From Day 1 through Week 28.

Other adverse events

Measure	Methotrexate n=31 participants at risk 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.	Tocilizumab + Methotrexate n=60 participants at risk 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.
Infections and infestations Upper respiratory tract infection	9.7% 3/31 • From Day 1 through Week 28.	6.7% 4/60 • From Day 1 through Week 28.
Infections and infestations Sinusitis	3.2% 1/31 • From Day 1 through Week 28.	8.3% 5/60 • From Day 1 through Week 28.
Infections and infestations Nasopharyngitis	6.5% 2/31 • From Day 1 through Week 28.	5.0% 3/60 • From Day 1 through Week 28.
Infections and infestations Urinary tract infection	6.5% 2/31 • From Day 1 through Week 28.	3.3% 2/60 • From Day 1 through Week 28.
Infections and infestations Bronchitis	0.00% 0/31 • From Day 1 through Week 28.	5.0% 3/60 • From Day 1 through Week 28.
Gastrointestinal disorders Nausea	3.2% 1/31 • From Day 1 through Week 28.	6.7% 4/60 • From Day 1 through Week 28.
Nervous system disorders Headache	0.00% 0/31 • From Day 1 through Week 28.	6.7% 4/60 • From Day 1 through Week 28.
Psychiatric disorders Anxiety	0.00% 0/31 • From Day 1 through Week 28.	5.0% 3/60 • From Day 1 through Week 28.
Skin and subcutaneous tissue disorders Rash	0.00% 0/31 • From Day 1 through Week 28.	5.0% 3/60 • From Day 1 through Week 28.

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER