Comparison of Disease Modifying Antirheumatic Drugs Therapy in Patients With RA Failing Methotrexate Monotherapy

Study Overview
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Brief Summary
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RA (Rheuatoid arthritis) is a multisystem disease that mainly involves joints resulting in destructive arthritis if not treated rapidly. Inspite of various advances in field of early diagnosis and treatment of RA, there is still a need for better understanding of the efficacy and safety of various combinations of conventional DMARDS, and to rank them in order accordingly, so as to give a clearer vision for further management of RA once MTX monotherapy fails, so as to achieve remission as soon as possible. The study will be conducted at the Department of Clinical Immunology, JIPMER (Jawaharlal Institute of Postgraduate Medical Education & Research). patients who fail methotrexate monotherapy will be randomised to 2 treatment arms - either a combination of Sulfasalazine (SSZ), Hydroxychloroquine (HCQ) and Methotrexate (MTX) or Leflunomide (LEF), Hydroxychloroquine (HCQ) and Methotrexate (MTX)

Detailed Description
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Patients aged ≥18 years, fulfilling the 2010 ACR EULAR criteria for RA (symptom duration less than two years) , having more than 4 joints involved & having moderate to severe disease activity (DAS28≥3.2) will be invited to participate. After providing written informed consent, eligible patients will be first started on MTX monotherapy & only patients who have persistant moderate disease activity (DAS28 ESR > 3.2) will be randomized into two groups. Block randomization will be done to generate random allocation sequence Group 1 - will receive MTX+LEF+HCQ Group 2- will receive MTX+SSZ+HCQ DMARD dosages used are: MTX 25 mg/week orally (dosage after 6 weeks),SSZ 2g/d (after 4 weeks) LEF 20 mg/day (dosage after 2 weeks) and HCQ 200 mg/day. Glucocorticoids will be given in an oral tapering scheme. All patients will be prescribed folic acid (10 mg/week) during MTX prescription.

Official Title
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Comparison of Sulfasalazine Versus Leflunomide Based Combination Disease Modifying Anti-rheumatic Drug Therapy (DMARD) in Patients With Rheumatoid Arthritis Failing Methotrexate Monotherapy : A Randomized Control Trial

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Leflunomide
* Drug: Hydroxychloroquine
* Drug: Prednisolone
* Drug: Folic Acid
* Drug: Sulfasalazine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years satisfying ACR-EULAR criteria for RA Polyarthritis (>4 joints) Disease duration of less than 2 years Patients with moderate to severe disease activity (DAS28>3.2) Patients who have failed to respond to initial Methotrexate monotherapy Exclusion Criteria: End stage disease (deformed fixed joints) Patients with vasculitis, extra-articular features like interstitial lung disease8 Contraindications to DMARD therapy (Chronic Alcoholism, Chronic liver disease, Evidence of acute/chronic infection, Chronic kidney disease, Patients with leucopenia (<3.0×109/l), thrombocytopenia (<150×109/l), AST/ALT>2× upper normal value and creatinine clearance <30ml/minute ) Pregnant, lactating women ; patients (both men and women) of reproductive age group unwilling for contraceptive use who have not completed the family Patients unable to come for regular follow up

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: group 1- MTX+LEF+HCQ<br>Active Comparator: Combination of Methotrexate (up to 25 mg per week), Leflunomide (20 mg once a day) and Hydroxychloroquine (200-400 mg once at night). All drugs are to be taken orally. Duration of therapy is for 3 months. All patients will receive folic acid (5 mg twice a week) along with methotrexate. Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop) will be given as bridging therapy. | Drug: Methotrexate<br>* Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases<br>* Other names: folitrax, MTX;Drug: Leflunomide<br>* Leflunomide inhibits pyrimidine synthesis, resulting in blockade of T-cell proliferation. Leflunomide is used in patients with moderate to severe active rheumatoid arthritis with early or late disease<br>* Other names: Arava, Lefno, LEF;Drug: Hydroxychloroquine<br>* Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.<br>* Other names: HCQ;Drug: Prednisolone<br>* Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop)<br>* Other names: Steroids, Glucocorticoids;Drug: Folic Acid<br>* Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.<br>* Other names: Folvite;|
| Active Comparator: group 2- MTX+SSZ+HCQ<br>Combination of Methotrexate (up to 25 mg per week), Sulfasalazine (2g per day) and Hydroxychloroquine (200-400 mg once at night). All drugs are to be taken orally. Duration of therapy is for 3 months. All patients will receive folic acid (5 mg twice a week) along with methotrexate. Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop) will be given as bridging therapy. | Drug: Methotrexate<br>* Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases<br>* Other names: folitrax, MTX;Drug: Hydroxychloroquine<br>* Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.<br>* Other names: HCQ;Drug: Prednisolone<br>* Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop)<br>* Other names: Steroids, Glucocorticoids;Drug: Folic Acid<br>* Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.<br>* Other names: Folvite;Drug: Sulfasalazine<br>* 5-aminosalicylic acid (5-ASA) is the active component of sulfasalazine; the specific mechanism of action of 5-ASA is unknown; however, it is thought that it modulates local chemical mediators of the inflammatory response, especially leukotrienes, and is also postulated to be a free radical scavenger or an inhibitor of tumor necrosis factor (TNF)<br>* Other names: Saaz, SSZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Good EULAR Response at the End of 12 Weeks | EULAR response criteria for Rheumatoid arthritis includes- estimation of DAS 28 ESR, that includes- Tender joint count 28 Swollen joint count 28 ESR Patient global assessment of health | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity as Per Ultrasound-7 (US-7) Score | Ultrasound 7 score (US-7) Calculates ultrasound score in 7 joints using greyscale and power doppler to evaluate for disease activity (synovitis, tenosynovitis) and damage (erosions) Score minimum value= 0 Maximum value = 108 Higher score indicates worse disease | 12 weeks | 
| Number of Participants With Adverse Drug Reactions | Infections, transaminitis, nausea, vomiting, derranged renal function tests etc | 24 weeks | 
| Indian Health Assessment Questionnaire (iHAQ) | Indian version of Health assessment Questionnaire (iHAQ) Comprises of 12 questions relating to functional activity iHAQ score ranges from 0 to 3 (minimum 0, maximum 3) Higher scores indicate more disability | 12 weeks |