MTX Discontinuation and Vaccine Response

• ClinicalTrials.gov Identifier: NCT02748785
• Recruitment Status: Completed
• First Posted: April 22, 2016
• Results First Posted: October 4, 2018
• Last Update Posted: October 4, 2018
• Sponsor: Seoul National University Hospital
• Information provided by (Responsible Party): Eun Bong Lee, Seoul National University Hospital

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.

Condition or disease	Intervention/treatment	Phase
Arthritis, Rheumatoid	Drug: Methotrexate; Biological: Seasonal Influenza vaccine	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 277 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Methotrexate Discontinuation on Efficacy of Seasonal Influenza Vaccination in Patients With Rheumatoid Arthritis: A Randomized Clinical Trial
• Study Start Date: September 2015
• Actual Primary Completion Date: August 2016
• Actual Study Completion Date: August 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1 (No MTX Hold before Vaccination); Group 1 will continue MTX	Drug: Methotrexate; Methotrexate will be continued; Biological: Seasonal Influenza vaccine; all subjects will be vaccinated with a seasonal influenza vaccine
Experimental: Group 2 (MTX hold 4 Weeks before vaccination); Group 2 will hold MTX 4 weeks before vaccination and resume MTX on the day of vaccination	Drug: Methotrexate; Methotrexate will be continued; Biological: Seasonal Influenza vaccine; all subjects will be vaccinated with a seasonal influenza vaccine
Experimental: Group 3 (MTX hold 2 Weeks before Vaccination); Group 3 will hold MTX 2 weeks before vaccination and resume MTX 2 weeks after vaccination	Drug: Methotrexate; Methotrexate will be continued; Biological: Seasonal Influenza vaccine; all subjects will be vaccinated with a seasonal influenza vaccine
Experimental: Group 4 (MTX hold on Day of Vaccination); Group 4 will hold MTX on day of vaccination and resume MTX 4 weeks after vaccination.	Drug: Methotrexate; Methotrexate will be continued; Biological: Seasonal Influenza vaccine; all subjects will be vaccinated with a seasonal influenza vaccine

Outcome Measures

Primary Outcome Measures :

1. Satisfactory Vaccination Responses Against 3 Antigens [ Time Frame: 8 weeks ]
   Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
2. Satisfactory Vaccination Responses Against > 2/3 Antigens [ Time Frame: 8 weeks ]
   Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
3. Satisfactory Vaccination Responses Against > 1/3 Antigens [ Time Frame: 8 weeks ]
   Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers

Secondary Outcome Measures :

1. Proportion of Seroprotection Against H1N1 [ Time Frame: 8 weeks ]
   Seroprotection is defined as antibody titers of ≥40
2. Proportion of Seroprotection Against H3N2 [ Time Frame: 8 weeks ]
   Seroprotection is defined as antibody titers of ≥40
3. Proportion of Seroprotection Against B-Yamagata [ Time Frame: 8 weeks ]
   Seroprotection is defined as antibody titers of ≥40
4. Change From Baseline in Antibody Titer Against H1N1 [ Time Frame: Day of and 4 weeks after vaccination ]
   Fold change = post-vaccination titer/pre-vaccination titer
5. Change From Baseline in Antibody Titer Against H3N2 [ Time Frame: Day of and 4 weeks after vaccination ]
   Fold change = post-vaccination titer/pre-vaccination titer
6. Change From Baseline in Antibody Titer Against B-Yamagata [ Time Frame: Day of and 4 weeks after vaccination ]
   Fold change = post-vaccination titer/pre-vaccination titer
7. DAS28 Flare Rate at Visit 4 [ Time Frame: 20 weeks from enrollment. ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Korea, Republic of

Seoul National University Hospital

Seoul, Korea, Republic of, 110-744

Sponsors and Collaborators

Seoul National University Hospital

More Information

Publications:

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Eun Bong Lee, Professor, Seoul National University Hospital
• ClinicalTrials.gov Identifier: NCT02748785
• Other Study ID Numbers: SNUH-IMJ-001
• First Posted: April 22, 2016
• Results First Posted: October 4, 2018
• Last Update Posted: October 4, 2018
• Last Verified: November 2017

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Methotrexate; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors