To understand the immunogenicity of Covisheild vaccine in patients with RA by discontinuing methotrexate temporarily
- Conditions
- Other rheumatoid arthritis with rheumatoid factor, (2) ICD-10 Condition: M45-M49||Spondylopathies, (3) ICD-10 Condition: M060||Rheumatoid arthritis without rheumatoid factor, (4) ICD-10 Condition: M061||Adult-onset Stills disease, (5) ICD-10 Condition: M315||Giant cell arteritis with polymyalgia rheumatica, (6) ICD-10 Condition: M30-M36||Systemic connective tissue disorders,
- Registration Number
- CTRI/2021/07/034639
- Lead Sponsor
- Centre for Arthritis and Rheumatism Excellence CARE
- Brief Summary
**1.** **BACKGROUNDand RATIONALE**
Autoimmune Rheumatic disease(AIRD) are chronic systemic inflammatory diseases requiring long term treatmentwith DMARDS ,among which Methotrexate is an important drug for management (1,2).These patients are moresusceptible to infections because of their underlying immune dysfunction andthe treatment-induced immune suppression.(3,4) Consequently, they arerecommended to receive vaccines against preventable diseases, especiallyagainst the current pandemic COVID 19.
However, theability of the patients on MTX to adequately respond to vaccines and the differences in humoral andcellular immune response to SARS-CoV-2 vaccination are not known, leaving asignificant gap in knowledge that prevents optimal management of this patientpopulation. Also, the period of time for which it should be discontinued is notclear. It is known that in special circumstances, such as life-threateninginfections, vaccination or major surgery, use of MTX should be minimized torestore treatment-associated immunosuppression [5,6].According to the ACRguidelines it is advised to withholdmethotrexate 1 week after each vaccine dose, for those with well-controlled disease.Our knowledge is confined to the data from influenza vaccine and pneumococcalvaccine(7,8,9) which showed that holding MTX for 2 weeks is associated withbetter vaccine response.
The effects of temporarydiscontinuation of methotrexate on antibody titers to the trivalent influenzavaccine were investigated in a prospective, randomized, parallel-group,single-blind, single-centre pilot study of 199 patients with rheumatoidarthritis who were taking stable methotrexate doses Patients were randomlyassigned to continue methotrexate(group 1; 54 patients), suspend methotrexate 4weeks before vaccination (group 2; 44 patients), suspend methotrexate 2 weeksbefore and 2 weeks after vaccination(group 3; 49 patients); or suspendmethotrexate 4 weeks after vaccination (group 4; 52 patients).All groups showeda similar frequency of satisfactory vaccine responses (≥4-times increase inantibody titer); however, group 3 achieved significantly higher vaccineresponses compared with group 1. Withholding methotrexate 4 weeks beforeinfluenza vaccination (group 2) was not associated with significantly differentantibody titers, whereas discontinuing methotrexate for 4 weeks aftervaccination (group 4) resulted in improvement compared with group 1. To reducethe risk of rheumatoid arthritis flares while achieving an adequate vaccineresponse, a shorter methotrexate discontinuation period was investigated in a prospective, multi-centrestudy in which patients with rheumatoid arthritis on stable methotrexate doseswere randomly assigned to continue methotrexate (156 patients) or withholdmethotrexate for 2 weeks (160 patients) after the quadrivalent influenzavaccine. Significantly more patients in the methotrexate-hold group achievedsatisfactory vaccine responses(≥4-times increase in antibody titre to at leasttwo of four influenza antigens) compared with the methotrexate-continue group(75·5% vs 54·5%; p<0.001; difference 21·0%, 95% CI 10·6–31·7%). Neither ofthese studies showed a significant increase in rheumatoid arthritis flaresafter discontinuation of methotrexate.
There are very few RCTs to prove this yet in COVID 19 vaccine except therecent study on
mRNA vaccine (BNT 17262) in patientswith immune mediated inflammatory diseases on methotrexate showed that MTX useadversely affected humoral and cellular immune response to COVID-19 mRNAvaccines(10) Hence it worthwhilestudying the immunogenicity to Covishield in stable subjects with vs without holding MTX .
In a recent study done at our centre CARE, it was found that the humoral immunogenicity of Covishield in autoimmunerheumatic diseases showed no statistically significant difference between thepatients on MTX with other DMARDs vs other DMARDs.As most of our patientscontinued Methotrexate during their Covid-19 vaccination and produced similarhumoral
response as in other DMARDS, the evidence for the recommendation fordiscontinuation of Methotrexate one week after Covid-19 vaccination has to bevalidated based on real world data with Randomized control trials
Hence, we study the effect oftemporary discontinuation of MTX for 2 weeks post Covishield vaccine doses onthe humoral and cellular immunogenicity at the end of 1 month post 2nddose of vaccination
.
**2.****STUDY SITE****:** Dr.Shenoy’sCare, Nettoor
**3.****STUDY DESIGN**:single centre Randomized Controlled trial
**4.****STUDY PERIOD:** Thisstudy will be conducted over a period of 6 months
**5.** **STUDYPOPULATION**
· Patients diagnosed as Autoimmune Rheumatic disease(AIRD) who are on stabledose of Methotrexate with or withoutDMARDs for the last 2 months with stable liver function tests and blood counts and is scheduled for COVID 19 vaccination, with no evidence ofCOVID infection
· The baseline SARS CoV 2anti Spike Ab titre will be measured to ensure that they are COVID 19 negative
**6.****STUDYOBJECTIVE**
**PrimaryObjective**
To compare theimmunogenicity of Covishield vaccination in patients with Autoimmune Rheumatic disease(AIRD) onmethotrexate discontinuation temporarily for 2 weeks after each dose of vaccine VS those continued on methotrexate .
**7.****INCLUSIONAND EXCLUSION CRITERIA**
**Inclusion Criteria**
· Patient above 18years of age.
· Patients willingto give consent for the study
· Patients with aprior diagnosis of Autoimmune Rheumaticdisease(AIRD)
stable dose for at least the past 2 months
**Exclusion Criteria**
· Patients who hadcovid-19 infection in the past.
· Patients withhistory of allergy to vaccine components .
· PriorGBS/demyelinating syndromes
· Any live vaccinetaken within prior 4 weeks or inactivated vaccine in last 2 weeks before study
**1.** **METHODS:**
· In this prospective randomised singlecentre study, patients with chronic stable AutoimmuneRheumatic disease(AIRD) onMTX with or without other DMARDs were randomly assigned at a ratio of 1:1 tocontinue MTX or to hold MTX for 2weeks after each dose of Covishield vaccine .Randomizationshall be done using block randomisation chart. A prior COVID infection shall beruled out by baseline anti SARS CoV 2 Spike antibody assay, which should benegative. .Baseline blood of about 7 ml would be withdrawn and will be storedfor future evaluation. A data collection form shall be used to capture detailsabout patients As primary objective the immunogenicity of Covishield vaccinebetween the two groups will be compared using statistical analysis
· After vaccination, patients in theMTX-continue group continued their MTX in their current dose, whereas patientsinthe MTX-hold group suspended it for 2weeks after each dose of vaccine and then resumes it at previous dose.
· 1month after second dose of Covishield vaccine, theserum of the patients will be collected and Covid19 antibody (spike antibody) /neutralisingAb will be assessed using CLIA at CARE LAB to test humoral immune response, ELIspotassay shall be done to test for cellular immune response
· The patients will be further followed uptill the next 6 months. Any patient found positive after enrolment will bewithdrawn from the study.
· RescueTherapy-Incase of flare of arthritis, short course low dose steroids and/or NSAIDs willbe considered till the second dose of vaccine
· The study isregistered with CTRI, protocol number:**CCR/RHEU /0003 /2021.**The study will be conducted in accordance with the principles of the Declarationof Helsinki and Good Clinical Practice guidelines. Written informed consent wasobtained from all patients before enrolment in the trial
**2.** **Outcomes**
The primary outcome i.e., the anti spike/neutralizing antibody titre andT cell ELIspot assay will be assessed 1 month after the second dose ofvaccine and to see if there is statistically significant difference among thetwo groups studied
**3.** **Statisticalanalysis**
The primaryanalysis population (per-protocol population)
included allstudy subjects who underwent the vaccination, discontinued or continued MTXaccording to the allocated regimen, and
whoseprevaccination and postvaccination titres were available
The samplesizing assumes that the expected percentage response in methotrexate hold groupis 75% and in methotrexate countinue group is 54%. To achieve 90% power todetect this difference with a significance level of 5% it is estimated that 104subjects per group would be required. With a withdrawal/non-evaluable subjectrate of 10% a total of 115 per group subjects will be recruited leading to atotal required sample size of 230 subjects.
The data will beassessed for the normality using Shapiro wilk test
Countionousvariables will be assessed either with t test or mann Whitney test asappropriately based on their normality .
Categoricalvariables will be assessed based on chi square test or fisher exact test
A P value lesserthan 0.05 will be considered as a statistically significant for our analysis
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Closed to Recruitment of Participants
- Sex
- All
- Target Recruitment
- 230
- Inclusion Criteria Patient above 18 years of age.
- Patients willing to give consent for the study Patients with a prior diagnosis of Autoimmune Rheumatic disease(AIRD) stable dose for at least the past 2 months.
- Exclusion Criteria Patients who had covid-19 infection in the past.
- Patients with history of allergy to vaccine components .
- Prior GBS/demyelinating syndromes Any live vaccine taken within prior 4 weeks or inactivated vaccine in last 2 weeks before study.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method the anti spike/neutralizing antibody titre and T cell ELIspot assay will be assessed 1 month after the second dose of vaccine and to see if there is statistically significant difference among the two groups studied 1 month post 2nd dose vaccine
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
Dr Shenoy’s Care Private Limited
🇮🇳Ernakulam, KERALA, India
Dr Shenoy’s Care Private Limited🇮🇳Ernakulam, KERALA, IndiaDr Padmanabha Shenoy DPrincipal investigator9446567000drdpshenoy@gmail.com