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This study will be conducted to find out how well a patient of rheumatoid arthritis (RA) will respond to disease-modifying antirheumatic drugs (DMARDs). RA is a chronic inflammatory arthritis, which leads to joint damage & disability if not treated properly. A DMARD is used to treat RA that slows down or prevents joint damage, as opposed to just relieve pain or inflammation by painkillers. The study will be conducted at the Department of Clinical Immunology, JIPMER (Jawaharlal Institute of Postgraduate Medical Education & Research). Patients will receive either a single DMARD (Methotrexate) or combination DMARDs therapy (Methotrexate + Leflunomide + Hydroxychloroquine). During treatment course, routine blood investigations will be carried out to monitor treatment response and side effects.
Patients aged ≥18 years, fulfilling the 2010 ACR EULAR criteria for RA (symptom duration less than one year) & having moderate to severe disease activity (DAS28≥3.2) will be invited to participate. After providing written informed consent, eligible patients will be stratified into two groups. Block randomization will be done to generate random allocation sequence.
Treatment Group I will be treated with Methotrexate (MTX) monotherapy and Treatment Group II will be treated with Methotrexate + Leflunomide (LEF) + Hydroxychloroquine (HCQ) combination therapy. Concurrent treatment with non-steroidal anti-inflammatory drugs in adequate dose and oral low dose Glucocorticoids (GC) (max: 15 mg/d) will be allowed during the study.
DMARD dosages used are: MTX 25 mg/week orally (dosage after 6 weeks), LEF 20 mg/day (dosage after 2 weeks) and HCQ 400 mg/day. GCs will be given in an oral tapering scheme. All patients will be prescribed folic acid (10 mg/week) during MTX prescription.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Combination therapy | 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: 15 mg/day, weeks 2-4: 10 mg/day, weeks 4-6: 5 mg/day and weeks 6-8: 2.5 mg/day then stop) will be given as bridging therapy. |
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| Monotherapy | Active Comparator | Methotrexate (up to 25 mg once a week) for 3 months. All patients will receive folic acid (5 mg twice a week) along with methotrexate. Low dose prednisolone (weeks 1-2: 15 mg/day, weeks 2-4: 10 mg/day, weeks 4-6: 5 mg/day and weeks 6-8: 2.5 mg/day then stop) will be given as bridging therapy. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methotrexate | Drug | Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic dise |
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| Measure | Description | Time Frame |
|---|---|---|
| A good response according to European league against rheumatism (EULAR) response criteria and Functional ability with Indian health assessment questionnaire (iHAQ) | A good response is defined as a decrease after randomization of disease activity score- 28 joints (DAS28) score by >1.2, and a resulting DAS28 score ≤ 3.2. Indian version of HAQ (iHAQ) has been validated in patients with RA, which comprises 12 questions (nine basic and three advanced activity of daily living) relevant to the Indian population. For each question there is a four-level difficulty scale ranging from 0 to 3 that represent no difficulty ('0'), some difficulty ('1'), much difficulty ('2'), and inability to do ('3'). The final score is the mean of the highest scores across the eight categories and ranges from 0 to 3, with higher levels indicating more disability. | 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| Mean changes over time in early morning stiffness (EMS) | 3 months | |
| Mean changes over time in erythrocyte sedimentation rate (ESR) | 3 months | |
| Disease activity as per ultrasound (US-7) score |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Vir S Negi, DM | Jawaharlal Institute of Postgraduate Medical Education & Research | Principal Investigator |
| Jignesh B Usdadiya, MD | Jawaharlal Institute of Postgraduate Medical Education & Research | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER) | Puducherry | Pondicherry UT | 605006 | India |
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| Leflunomide | Drug | 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 |
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| Hydroxychloroquine | Drug | Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine. |
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| Prednisolone | Drug | Low dose prednisolone (weeks 1-2: 15 mg/day, weeks 2-4: 10 mg/day, weeks 4-6: 5 mg/day and weeks 6-8: 2.5 mg/day then stop) |
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| Folic Acid | Drug | Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. |
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| 3 months |
| Radiographic progression assessed with Simple Erosion Narrowing Score (SENS) | 3 months |
| Adverse drug reactions | 3 months |
| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D008727 | Methotrexate |
| D000077339 | Leflunomide |
| D006886 | Hydroxychloroquine |
| D011239 | Prednisolone |
| D013256 | Steroids |
| D005938 | Glucocorticoids |
| D005492 | Folic Acid |
| ID | Term |
|---|---|
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D007555 | Isoxazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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