MTX Discontinuation and Vaccine Response
Primary Purpose
Arthritis, Rheumatoid
Status
Completed
Phase
Phase 4
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Methotrexate
Seasonal Influenza vaccine
Sponsored by
About this trial
This is an interventional treatment trial for Arthritis, Rheumatoid
Eligibility Criteria
Inclusion Criteria:
- Males or females > 18 years at time of consent
- Have a diagnosis of RA per ACR criteria
- Must understand and voluntarily sign an informed consent form including writing consent for data protection
- Stable doses of methotrexate over the preceding 6 weeks
Exclusion Criteria:
- Pregnant or lactating females
- Previous anaphylactic response to vaccine components or to egg.
- Acute infection with T >38°C at the time of vaccination
- History of Guillain-Barre syndrome or demyelinating syndromes
- Previous vaccination with any live vaccine 4 weeks before or any inactivated vaccine 2 weeks before the study
- Blood transfusion within 6 months
- Active rheumatoid arthritis necessitating a recent change in the drug regimen
- Any other rheumatic disease such as systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis/polymyositis, and vasculitis except for secondary Sjogren's disease
Sites / Locations
- Seoul National University Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Group 1 (No MTX Hold before Vaccination)
Group 2 (MTX hold 4 Weeks before vaccination)
Group 3 (MTX hold 2 Weeks before Vaccination)
Group 4 (MTX hold on Day of Vaccination)
Arm Description
Group 1 will continue MTX
Group 2 will hold MTX 4 weeks before vaccination and resume MTX on the day of vaccination
Group 3 will hold MTX 2 weeks before vaccination and resume MTX 2 weeks after vaccination
Group 4 will hold MTX on day of vaccination and resume MTX 4 weeks after vaccination.
Outcomes
Primary Outcome Measures
Satisfactory Vaccination Responses Against 3 Antigens
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Satisfactory Vaccination Responses Against > 2/3 Antigens
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Satisfactory Vaccination Responses Against > 1/3 Antigens
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Secondary Outcome Measures
Proportion of Seroprotection Against H1N1
Seroprotection is defined as antibody titers of ≥40
Proportion of Seroprotection Against H3N2
Seroprotection is defined as antibody titers of ≥40
Proportion of Seroprotection Against B-Yamagata
Seroprotection is defined as antibody titers of ≥40
Change From Baseline in Antibody Titer Against H1N1
Fold change = post-vaccination titer/pre-vaccination titer
Change From Baseline in Antibody Titer Against H3N2
Fold change = post-vaccination titer/pre-vaccination titer
Change From Baseline in Antibody Titer Against B-Yamagata
Fold change = post-vaccination titer/pre-vaccination titer
DAS28 Flare Rate at Visit 4
DAS28 flare rate at visit 4 as compared to visit 1. RA flare was defined as an increase in DAS28 of >1.2 (or >0.6 if the baseline DAS28 was ≥3.2).
Full Information
NCT ID
NCT02748785
First Posted
September 8, 2015
Last Updated
November 29, 2017
Sponsor
Seoul National University Hospital
1. Study Identification
Unique Protocol Identification Number
NCT02748785
Brief Title
MTX Discontinuation and Vaccine Response
Official Title
Effect of Methotrexate Discontinuation on Efficacy of Seasonal Influenza Vaccination in Patients With Rheumatoid Arthritis: A Randomized Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
September 2015 (undefined)
Primary Completion Date
August 2016 (Actual)
Study Completion Date
August 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seoul National University Hospital
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
To investigate whether a short term discontinuation of methotrexate (MTX) will improve the vaccination efficacy to seasonal influenza vaccination without deteriorating RA disease activity in a randomized clinical trial.
Detailed Description
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects the joints as the main target of the inflammation. Patients with RA require chronic treatment with disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), which constitutes the mainstay of treatment.
Underlying immune dysfunction and the additional immune suppression associated with treatment render patients with RA more susceptible to infection. Thus, vaccination against preventable diseases including influenza, pneumococcal pneumonia and hepatitis B is recommended for all RA patients who are subject to treatment with immunesupprssive drugs, unless there is a contraindication to the use of vaccination. However, low dose of glucocorticoids, conventional DMARDs and biological DMARDs including tumor necrosis factor inhibitors have been reported to substantially decrease vaccine response (4); MTX has been reported to be associated with a decreased response to seasonal influenza vaccination by up to 15%.
To optimize a vaccine response, vaccination should be administrated before the treatment with immunesuppressive medications is initiated. However, most patients with RA are already on stable dose of DMARDs at the time of when vaccinations, especially vaccine against seasonal influenza that needs annual administration, are considered. Alternatively, temporarily discontinuation of DMARDs might restore normal immune response to and so improve the efficacy of vaccination.
Although a short term discontinuation of DMARDs during perioperative period has not been associated with increased disease activity the longer discontinuation of DMARDs might lead to a significant aggravation of RA disease activity. To optimize the vaccine response, a short term discontinuation of DMARDs could be considered if this approach proves to be safe and effective.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arthritis, Rheumatoid
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
277 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group 1 (No MTX Hold before Vaccination)
Arm Type
Experimental
Arm Description
Group 1 will continue MTX
Arm Title
Group 2 (MTX hold 4 Weeks before vaccination)
Arm Type
Experimental
Arm Description
Group 2 will hold MTX 4 weeks before vaccination and resume MTX on the day of vaccination
Arm Title
Group 3 (MTX hold 2 Weeks before Vaccination)
Arm Type
Experimental
Arm Description
Group 3 will hold MTX 2 weeks before vaccination and resume MTX 2 weeks after vaccination
Arm Title
Group 4 (MTX hold on Day of Vaccination)
Arm Type
Experimental
Arm Description
Group 4 will hold MTX on day of vaccination and resume MTX 4 weeks after vaccination.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
Methotrexate will be continued
Intervention Type
Biological
Intervention Name(s)
Seasonal Influenza vaccine
Intervention Description
all subjects will be vaccinated with a seasonal influenza vaccine
Primary Outcome Measure Information:
Title
Satisfactory Vaccination Responses Against 3 Antigens
Description
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Time Frame
8 weeks
Title
Satisfactory Vaccination Responses Against > 2/3 Antigens
Description
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Time Frame
8 weeks
Title
Satisfactory Vaccination Responses Against > 1/3 Antigens
Description
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Proportion of Seroprotection Against H1N1
Description
Seroprotection is defined as antibody titers of ≥40
Time Frame
8 weeks
Title
Proportion of Seroprotection Against H3N2
Description
Seroprotection is defined as antibody titers of ≥40
Time Frame
8 weeks
Title
Proportion of Seroprotection Against B-Yamagata
Description
Seroprotection is defined as antibody titers of ≥40
Time Frame
8 weeks
Title
Change From Baseline in Antibody Titer Against H1N1
Description
Fold change = post-vaccination titer/pre-vaccination titer
Time Frame
Day of and 4 weeks after vaccination
Title
Change From Baseline in Antibody Titer Against H3N2
Description
Fold change = post-vaccination titer/pre-vaccination titer
Time Frame
Day of and 4 weeks after vaccination
Title
Change From Baseline in Antibody Titer Against B-Yamagata
Description
Fold change = post-vaccination titer/pre-vaccination titer
Time Frame
Day of and 4 weeks after vaccination
Title
DAS28 Flare Rate at Visit 4
Description
DAS28 flare rate at visit 4 as compared to visit 1. RA flare was defined as an increase in DAS28 of >1.2 (or >0.6 if the baseline DAS28 was ≥3.2).
Time Frame
20 weeks from enrollment.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Males or females > 18 years at time of consent
Have a diagnosis of RA per ACR criteria
Must understand and voluntarily sign an informed consent form including writing consent for data protection
Stable doses of methotrexate over the preceding 6 weeks
Exclusion Criteria:
Pregnant or lactating females
Previous anaphylactic response to vaccine components or to egg.
Acute infection with T >38°C at the time of vaccination
History of Guillain-Barre syndrome or demyelinating syndromes
Previous vaccination with any live vaccine 4 weeks before or any inactivated vaccine 2 weeks before the study
Blood transfusion within 6 months
Active rheumatoid arthritis necessitating a recent change in the drug regimen
Any other rheumatic disease such as systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis/polymyositis, and vasculitis except for secondary Sjogren's disease
Facility Information:
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
12. IPD Sharing Statement
Citations:
PubMed Identifier
12355475
Citation
Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002 Sep;46(9):2287-93. doi: 10.1002/art.10524.
Results Reference
background
PubMed Identifier
25587634
Citation
McMahan ZH, Bingham CO 3rd. Effects of biological and non-biological immunomodulatory therapies on the immunogenicity of vaccines in patients with rheumatic diseases. Arthritis Res Ther. 2014 Dec 23;16(6):506. doi: 10.1186/s13075-014-0506-0.
Results Reference
background
PubMed Identifier
25795907
Citation
Winthrop KL, Silverfield J, Racewicz A, Neal J, Lee EB, Hrycaj P, Gomez-Reino J, Soma K, Mebus C, Wilkinson B, Hodge J, Fan H, Wang T, Bingham CO 3rd. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann Rheum Dis. 2016 Apr;75(4):687-95. doi: 10.1136/annrheumdis-2014-207191. Epub 2015 Mar 20.
Results Reference
background
PubMed Identifier
28468794
Citation
Park JK, Lee MA, Lee EY, Song YW, Choi Y, Winthrop KL, Lee EB. Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 2017 Sep;76(9):1559-1565. doi: 10.1136/annrheumdis-2017-211128. Epub 2017 May 3.
Results Reference
derived
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MTX Discontinuation and Vaccine Response
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