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

Phase 3

Terminated

Conditions: Rheumatoid Arthritis

Interventions: Drug: Methotrexate
Drug: Leflunomide
Drug: Hydroxychloroquine
Drug: Prednisolone
Drug: Folic Acid
Drug: Sulfasalazine

Registration Number: NCT02930343

Lead Sponsor: Jawaharlal Institute of Postgraduate Medical Education & Research

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 136

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
group 1- MTX+LEF+HCQ	Methotrexate	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.
group 1- MTX+LEF+HCQ	Leflunomide	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.
group 1- MTX+LEF+HCQ	Hydroxychloroquine	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.
group 1- MTX+LEF+HCQ	Folic Acid	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.
group 1- MTX+LEF+HCQ	Prednisolone	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.
group 2- MTX+SSZ+HCQ	Hydroxychloroquine	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.
group 2- MTX+SSZ+HCQ	Methotrexate	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.
group 2- MTX+SSZ+HCQ	Prednisolone	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.
group 2- MTX+SSZ+HCQ	Folic Acid	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.
group 2- MTX+SSZ+HCQ	Sulfasalazine	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.

Primary Outcome Measures

Name	Time	Method
Number of Patients Achieving Good EULAR Response at the End of 12 Weeks	12 weeks	EULAR response criteria for Rheumatoid arthritis includes- estimation of DAS 28 ESR, that includes- 1. Tender joint count 28 2. Swollen joint count 28 3. ESR 4. Patient global assessment of health

Secondary Outcome Measures

Name	Time	Method
Disease Activity as Per Ultrasound-7 (US-7) Score	12 weeks	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
Number of Participants With Adverse Drug Reactions	24 weeks	Infections, transaminitis, nausea, vomiting, derranged renal function tests etc
Indian Health Assessment Questionnaire (iHAQ)	12 weeks	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