Title: Vaccine Response On/off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response?- A Randomised Controlled Trial
Funder: Medical Research Council

Abstract: The purpose of this study is to find out if a two-week break in taking methotrexate immediately after a person receives the Covid-19 booster-vaccine improves the immune response to vaccination in people with inflammatory conditions treated with this medicine. The study will also help understand the way in which methotrexate dampens the immune response to vaccines._x000D_ _x000D_ Methotrexate is the first-line treatment for inflammatory conditions such as rheumatoid arthritis and psoriasis. It does a good job at controlling such diseases but it also reduces the body’s ability to fight infections. People taking methotrexate also don’t get great responses to vaccines such as those against the flu and pneumonia. A study from Korea shows that a two-week break in methotrexate treatment after the flu vaccine increases the immune response to it. It is not known if such an interruption in treatment would improve the protection provided by vaccines against Covid-19. Better immunity usually means a better chance of not getting infected and fighting the virus if infected. Because there is no clear evidence on whether to halt or continue methotrexate during Covid-19 vaccinations, specialists have given conflicting advice that has confused patients. There is an opportunity to answer this question during the booster vaccinations in winter 2021._x000D_ _x000D_ We will invite 560 people with inflammatory conditions such as rheumatoid arthritis and psoriasis receiving methotrexate to take part in our study. Potential participants will be approached by their own specialists by post. Those eligible will be asked to attend their local hospital for their consent, simple research assessments, and to give a blood sample before the booster vaccine._x000D_ _x000D_ Participants will be asked to contact the study team by phone once they have a date for the booster. During the phone call, the study team will advise them to either interrupt methotrexate treatment for two weeks after the booster has been given or to carry on with methotrexate as usual. The decision on who pauses methotrexate and who carries on will be taken using a computerised system that allocates participants to either option by chance._x000D_ _x000D_ Participants will attend their usual hospital four week and twelve weeks after the booster vaccination to undergo assessments about their health and to give blood samples. The blood samples will be used to assess the immune response. We also want to make sure that the inflammatory condition does not get worse, so we will also check whether there has been a disease flare-up, and compare quality of life between the groups._x000D_ _x000D_ Blood samples from one hundred participants will be further analysed to understand more about the quality of immune response in detail._x000D_ _x000D_ PPI volunteers have reviewed the project and advised on the study design. They will continue to advise throughout the project, including reviewing study information, recruitment methods and helping the study team to understand the results and to share them widely with others._x000D_ _x000D_ The study findings will be disseminated to patients, public, healthcare professionals, and policy makers including the Joint Committee on Vaccinations and Immunisation and professional medical societies. The results will shape clinical practice in the UK and also worldwide.

Lay abstract: Question: Does interrupting low-dose methotrexate treatment for two weeks after SARS-CoV-2 vaccine booster improve the immune response to it, and what are the underlying mechanisms?_x000D_ _x000D_ Background: Low-dose methotrexate has emerged as the first line systemic therapy for chronic inflammatory conditions such as rheumatoid arthritis and psoriasis. However, its inhibitory effects on lymphocyte function causes suboptimal vaccine immunogenicity. A brief two-week treatment interruption after vaccination with the influenza vaccine protected 46% participants against all included strains compared to 22% participants with continued treatment. It is unknown if such a treatment interruption would improve immunity to vaccines against the SARS-CoV-2. This uncertainty resulted in conflicting advice from specialist societies, anxiety among patients, and may be addressed during the booster vaccinations in winter 2021._x000D_ _x000D_ Aim: To examine the effects of a two-week interruption in low-dose methotrexate treatment (upto 25 mg/week) after SARS-CoV-2 vaccine booster on vaccine immunogenicity in people with inflammatory conditions._x000D_ _x000D_ Study design: Prospective, parallel group, randomised controlled trial with internal feasibility assessment, and nested mechanistic study. Setting: Secondary care_x000D_ _x000D_ Population: Adults (age 18 years or more) with stable inflammatory disease, on low-dose weekly methotrexate, able to interrupt treatment for two weeks according to their consultant._x000D_ _x000D_ Randomisation: 1:1 individual randomisation. Minimised by inflammatory conditions, age (40 year or less, 41-64 year, 65 year or more), SARS-CoV-2 vaccine received in current vaccination cycle (mRNA vs. other)._x000D_ _x000D_ Intervention: Advice to withhold methotrexate for two weeks post SARS-Cov-2 vaccine booster. _x000D_ Comparator: To continue with methotrexate as usual._x000D_ _x000D_ Outcomes:_x000D_ Primary: Anti-spike receptor binding domain (RBD) antibody at week 4._x000D_ Secondary: Anti-spike-RBD antibody at week 12; disease flare up, disease activity, treatment changes, quality of life at weeks 4 and 12._x000D_ Mechanistic: Antibody neutralisation titres at weeks 4 and 12; effects of methotrexate adherence using validated bioassay on immunological outcomes._x000D_ _x000D_ Research contact: 1] Pre-booster: consent, research assessments, blood collection. 2] Randomisation (phone): reconfirm eligibility, assess global disease activity. 3] Weeks 1, 2 (SMS): adherence to intervention, global disease activity (only week 2). 4] Weeks 4, 12: research assessment, blood collection._x000D_ _x000D_ Analysis: Multi-level mixed effects models adjusted for randomisation factors and important prognostic factors using the as randomised population._x000D_ _x000D_ Sample size: 560 participants (280 in each arm) will allow detection of an absolute difference of 25% anti-spike-RBD antibody, using 90%, 2-sided a=5% and 10% loss to follow up. 100 participants (50 in each arm) will participate in the mechanistic sub-study and provide additional blood samples for methotrexate adherence biomarker and neutralisation assay._x000D_ _x000D_ Timeline: Set-up: months 1-3; Recruitment: months 4-16; Laboratory analysis: months 6 to 21; Data analysis: months 15-24. Write-up: months 21-24._x000D_ _x000D_ Impact and dissemination: The findings will be disseminated to patients, the public, policy makers including the Joint Committee on Vaccinations and Immunisation, and Rheumatology and Dermatology societies where they will influence clinical practice.

Research activity codes: 3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM